(Progress in Brain Research Volume 223) Ekhtiari, Hamed - Paulus, Martin-Neuroscience For Addiction Medicine - From Prevention To Rehabilitation - Constructs and Drugs-Elsevier (2016) PDF

Serial Editor
Vincent Walsh
Institute of Cognitive Neuroscience
University College London
17 Queen Square
London WC1N 3AR UK
Editorial Board
Mark Bear, Cambridge, USA.

Medicine & Translational Neuroscience
Hamed Ekhtiari, Tehran, Iran.
Addiction
Hajime Hirase, Wako, Japan.
Neuronal Microcircuitry
Freda Miller, Toronto, Canada.
Developmental Neurobiology
Shane O’Mara, Dublin, Ireland.
Systems Neuroscience
Susan Rossell, Swinburne, Australia.
Clinical Psychology & Neuropsychiatry
Nathalie Rouach, Paris, France.
Neuroglia
Barbara Sahakian, Cambridge, UK.
Cognition & Neuroethics
Bettina Studer, Dusseldorf, Germany.
Neurorehabilitation
Xiao-Jing Wang, New York, USA.
Computational Neuroscience
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Contributors
Mustafa al’Absi
University of Minnesota School of Medicine, Duluth, MN, USA
Nelly Alia-Klein
Department of Psychiatry, and Department of Neuroscience, Icahn School of
Medicine at Mount Sinai, New York, NY, USA
Barbara C. Banz
Department of Psychiatry, Yale University School of Medicine, New Haven, CT,
USA
Lucia Bederson
Department of Psychology, New York University, New York, NY, USA
Wade Berrettini
Karl E Rickles Professor of Psychiatry, Center for Neurobiology and Behavior,
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Warren K. Bickel
Addiction Recovery Research Center, Virginia Tech Carilion Research Institute,
Roanoke, VA, USA
Jean Lud Cadet
Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural
Research Program, National Institutes of Health, Baltimore, MD, USA
Bader Chaarani
Department of Psychiatry, Vermont Center on Behavior and Health, University of
Vermont, Burlington, VT, USA
Kelly E. Courtney
Department of Psychology, University of California, Los Angeles, CA, USA
W. Miles Cox
Bangor University, Bangor, UK
Anita Cservenka
Departments of Psychiatry, Oregon Health & Science University, Portland, OR,
USA
Manoranjan S. D’Souza
Department of Biomedical and Pharmaceutical Sciences, The Raabe College of
Pharmacy, Ohio Northern University, Ada, OH, USA
Scott Edwards
Department of Physiology, Alcohol and Drug Abuse Center of Excellence,
Neuroscience Center of Excellence, Louisiana State University Health Sciences
Center, New Orleans, LA, USA
v
vi Contributors
Hamed Ekhtiari
Research Center for Molecular and Cellular Imaging; Neurocognitive Laboratory,
Iranian National Center for Addiction Studies (INCAS); Translational
Neuroscience Program, Institute for Cognitive Sciences Studies (ICSS), and
Neuroimaging and Analysis Group, Research Center for Molecular and Cellular
Imaging (RCMCI), Tehran University of Medical Sciences, Tehran, Iran
Javad Salehi Fadardi
Ferdowsi University of Mashhad; Bangor University, Bangor, UK, and Addiction
Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran
Shelly B. Flagel
Department of Psychiatry, and Molecular and Behavioral Neuroscience Institute,
University of Michigan, Ann Arbor, MI, USA
John J. Foxe
Department of Pediatrics, and Department of Neuroscience, Albert Einstein
College of Medicine, Bronx, NY, USA
Hugh Garavan
Department of Psychiatry, Vermont Center on Behavior and Health, and
Department of Psychological Science, University of Vermont, Burlington, VT, USA
Ashley N. Gearhardt
Department of Psychology, University of Michigan, Ann Arbor, MI, USA
Rita Z. Goldstein
Colleen A. Hanlon
Medical University of South Carolina, Charleston, SC, USA
Kelsey E. Hudson
Andrine Lemieux
Francesco Leri
Department of Psychology, University of Guelph, Guelph, ON, Canada
Scott J. Moeller
Seyed Mohammad Ahmadi Soleimani
Neurocognitive Laboratory, Iranian National Center for Addiction Studies
(INCAS), Tehran University of Medical Sciences, and Department of Physiology,
Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
Azarkhsh Mokri
Clinical Department, Iranian National Center for Addiction Studies (INCAS),
Tehran University of Medical Sciences, Tehran, Iran
Contributors vii
John Monterosso
Neuroscience Graduate Program; Department of Psychology, and Brain and
Creativity Institute, University of Southern California, Los Angeles, CA, USA
Jonathan D. Morrow
Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA
Bonnie J. Nagel
Departments of Psychiatry, and Behavioral Neuroscience, Oregon Health &
Science University, Portland, OR, USA
Padideh Nasseri
(INCAS), Tehran University of Medical Sciences, and Translational Neuroscience
Program, Institute for Cognitive Science Studies (ICSS), Tehran, Iran
Marc N. Potenza
Department of Psychiatry; Department of Neurobiology, Child Study Center, and
CASAColumbia, and Connecticut Mental Health Center, Yale University School of
Medicine, New Haven, CT, USA
Alexandra Potter
Amanda J. Quisenberry
Roanoke, VA, USA
Arash Rahmani
Iranian National Center for Addiction Studies, Tehran University of Medical
Sciences, Tehran, Iran
Lara A. Ray
Erica M. Schulte
Department of Psychology, University of Michigan, Ann Arbor, MI, USA
Sarah E. Snider
Roanoke, VA, USA
Philip A. Spechler
Jeffrey S. Stein
Roanoke, VA, USA
Jane R. Taylor
Department of Psychiatry, Yale University, New Haven, CT, USA
viii Contributors
Mary M. Torregrossa
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
Yvonne H.C. Yau
Department of Neurology and Neurosurgery, Montreal Neurological Institute,
McGill University, and Montreal Neurological Institute, 3801 Rue University,
Montréal, QC, Canada
Fatemeh Yavari
(INCAS), Tehran University of Medical Sciences, Tehran, Iran
Sarah W. Yip
Department of Psychiatry, Yale University School of Medicine, New Haven, CT,
USA
Sonja Yokum
Oregon Research Institute, Eugene, OR, USA
Yan Zhou
The Laboratory of the Biology of Addictive Diseases, The Rockefeller University,
New York, NY, USA
Preface: Neuroscience for Addiction
Medicine: From Prevention to
Rehabilitation
It is estimated that a total of 246 million people, i.e., over 5% of the world’s adult
population, have used an illicit drug during the last year. Meanwhile, more than 10%
of these drug users are suffering from drug use disorders and the number of drug-
related deaths is estimated to be over 187,000 annually (UN Office of Drugs and
Crime, 2015). Adding disorders related to the nonpharmacologic or behavioral ad-
dictions such as pathological gambling, Internet and gaming addictions, overeating
and obesity, and compulsive sexual behaviors to the drug addictions comprises a
group of brain disorders that contribute as one of the major challenges for humankind
in the current millennium.
Addiction medicine has been regarded as a stand-alone specialty among other
medical professions in several countries; however, there are still serious concerns
regarding the availability and effectiveness of interventions in a wide range from pre-
vention to rehabilitation in addiction medicine. Accumulating pathophysiological
evidences for “Addiction as a Brain Disorder” during last 20 years is extending ex-
pectations from neuroscience to contribute more seriously in the routine clinical
practices during prevention, assessment, treatment, and rehabilitation of addictive
disorders. Neuroscience has made tremendous progress toward understanding basic
neural processes; however, there is still a lot of progress needed to be made in uti-
lizing neuroscience approaches in clinical medicine in general and addiction medi-
cine in particular.
The basic idea of a book to provide the current status of the field of neuroscience
of addiction with particular emphasis on potential applications in a clinical setting
was jumped out during meetings in the 2nd Basic and Clinical Neuroscience Con-
gress in October 2013 in Tehran with Professor Vincent Walsh, the Progress in Brain
Research, PBR, Editor in Chief. We, Martin and Hamed, started to work together for
a proposal to the PBR advisory board to compile a volume of reviews in June 2014 in
the Laureate Institute for Brain Research, Tulsa, OK. After receiving the green lights
from the PBR office, the invitations went out to the senior scholars in the field from
October 2014. We received overwhelming positive feedbacks from over 120 contrib-
utors from 90 institutes in 14 countries that ended up with 36 chapters in two volumes
in October 2015. During this 1 year of intensive efforts, all the chapters were peer
reviewed and revised accordingly to meet high-quality standards of the PBR and our
vision for the whole concept of the volumes. The first volume, PBR Vol. 223, is
mainly focused on the basic neurocognitive constructs contributing to pathophysio-
logical basis of pharmacological and behavioral addictions, and the second volume,
PBR Vol. 224, depicts the contribution of neuroscience methods and interventions in
the future of clinical practices in addiction medicine.
xix
xx Preface: Neuroscience for addiction medicine
The goal of these two volumes is to provide readers with insights into current
gaps and possible directions of research that would address impactful questions.
The fundamental question that is addressed in these volumes is “how can neurosci-
ence be used to make a real difference in addiction medicine”? To that end, we asked
the contributors to:
(1) review the recent literature with a time horizon of approximately 5–10 years,
(2) identify current gaps in our knowledge that contribute to the limited impact of
the area of research to clinical practice, and
(3) provide a perspective where the field is heading and how impactful questions can
be addressed to change the practice of addiction medicine.
We envision that both neuroscientists and clinical investigators will be the primary
audience of these two volumes. Moreover, the common interest of these individuals
will be the application of neuroscience approaches in studies to assess or treat indi-
viduals with addictive disorders. We think that these PBR volumes will provide the
audiences with most recent evidences from different disciplines in brain studies on
the wide range of addictive disorders in an integrative way toward “Neuroscience for
Addiction Medicine: From Prevention to Rehabilitation.” The hope is that the infor-
mation provided in the series of chapters in these two volumes will trigger new re-
searches that will help to connect basic neuroscience to clinical addiction medicine.
The Editors
Hamed Ekhtiari, MD,
Iranian National Center for Addiction Studies
Martin Paulus, MD,
Laureate Institute for Brain Research
REFERENCE
UN Office of Drugs and Crime, 2015. World Drug Report 2015. United Nation Publication,
Vienna.
CHAPTER
Neuroscience of resilience
and vulnerability for
addiction medicine:
From genes to behavior
1
Jonathan D. Morrow*,1, Shelly B. Flagel*,†
*Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA
†
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
1
Corresponding author: Tel.: +1-734-764-0231; Fax: +1-734-232-0244,
e-mail address: [email protected]
Abstract
Addiction is a complex behavioral disorder arising from roughly equal contributions of genetic
and environmental factors. Behavioral traits such as novelty-seeking, impulsivity, and cue-
reactivity have been associated with vulnerability to addiction. These traits, at least in part,
arise from individual variation in functional neural systems, such as increased striatal dopa-
minergic activity and decreased prefrontal cortical control over subcortical emotional and mo-
tivational responses. With a few exceptions, genetic studies have largely failed to consistently
identify specific alleles that affect addiction liability. This may be due to the multifactorial
nature of addiction, with different genes becoming more significant in certain environments
or in certain subsets of the population. Epigenetic mechanisms may also be an important
source of risk. Adolescence is a particularly critical time period in the development of addic-
tion, and environmental factors at this stage of life can have a large influence on whether inher-
ited risk factors are actually translated into addictive behaviors. Knowledge of how individual
differences affect addiction liability at the level of genes, neural systems, behavioral traits, and
sociodevelopmental trajectories can help to inform and improve clinical practice.
Keywords
Addiction, Individual differences, Cue-reactivity, Impulsivity, Dopamine, Neural circuits,
Genetics
There is considerable variability in the likelihood of developing addiction upon

exposure to drugs of abuse. This is evidenced by the fact that over 90% of Americans
have used alcohol, but only 8–12% ever meet criteria for alcohol dependence
(Anthony et al., 1994). Determining what factors render certain individuals more
Progress in Brain Research, Volume 223, ISSN 0079-6123, http://dx.doi.org/10.1016/bs.pbr.2015.09.004

© 2016 Elsevier B.V. All rights reserved.
3
4 CHAPTER 1 Neuroscience of resilience and vulnerability
susceptible to addiction has proven difficult to discern because of the array of vari-
ables involved. Over the past few decades, we have learned that there is a complex
interplay of genes and environment that govern the neurobiological and behavioral
processes relevant to addiction. However, there are, unquestionably, multiple algo-
rithms by which these factors may be combined to alter addiction liability. Below we
will briefly review findings from both human and animal studies that highlight some
of the behavioral, neural, and genetic variables believed to contribute to addiction
liability.
1 BEHAVIORAL TRAITS
Despite the oft-repeated adage that “there is no addictive personality,” there is a clear
association between addiction and certain personality traits. For example, clinical
studies have found that the trait known as neuroticism or negative emotionality is
associated with substance use disorders as well as depressive and anxiety disorders
(Kotov et al., 2010; Terracciano et al., 2008). The mechanisms underlying this as-
sociation are not well-characterized, but are thought to include increased stress sen-
sitivity (Ersche et al., 2012). Another personality trait associated with addiction is the
“externalizing” phenotype, characterized by novelty- and sensation-seeking behav-
ior, hypersensitivity to rewards, and insensitivity to punishment (Dick et al., 2013;
Hicks et al., 2013; Pingault et al., 2013). Evidence from animal models suggests that
the sensation-seeking trait may specifically increase the propensity to initiate and
continue drug use, as opposed to predisposing toward compulsive use that would
meet criteria for substance dependence (Belin et al., 2008; Deroche-Gamonet
et al., 2004; Piazza et al., 1989), and some human studies have substantiated this find-
ing (Ersche et al., 2013). Trait impulsivity, otherwise known as disinhibition or lack
of constraint, has perhaps the strongest evidence for an association with addiction.
In the animal literature, the transition to compulsive drug use can be predicted by
measures of impulsivity (Belin et al., 2008; Dalley et al., 2007); specifically the
inability to withhold a prepotent response (e.g., 5-choice serial reaction time task).
Similar tasks have been used with human subjects in the laboratory to assess
disinhibition or lack of constraint—and, in agreement with the rodent studies, these
studies have largely shown evidence for an association between trait impulsivity and
addiction (for review, see Verdejo-Garcia et al., 2008). Another addiction-related
trait is “cue-reactivity”; perhaps not surprisingly, as relapse is most often triggered
by cues (e.g., people, places, paraphernalia) in the environment that have been
previously associated with the drug-taking experience. Indeed, both human studies
and animal models suggest that individuals for whom the cue attains incentive
motivational value or incentive salience are the individuals most likely to exhibit re-
lapse (e.g., see Carter and Tiffany, 1999; Janes et al., 2010; Rohsenow et al., 1990;
Saunders and Robinson, 2010, 2011). These different personality traits have not only
been associated with different phases of addiction but also with different types of
drugs of abuse. For example, cocaine addicts tend to be more impulsive than heroin
3 Genetics 5
addicts; whereas heroin addicts are more anxious than cocaine addicts (Bornovalova
et al., 2005; Lejuez et al., 2005, 2006). These data beg the question of whether
certain personality traits predispose an individual to a particular phase (e.g., initiation
vs. relapse) of addiction or type of drug (e.g., psychostimulants vs. opioids), or if
it is the drugs themselves—via alteration of brain function—that cause the behav-
ioral traits.
2 NEUROBIOLOGICAL FACTORS
Although it has been difficult to parse cause from consequence when it comes to elu-
cidating the neurobiological mechanisms underlying addiction, there is general
agreement as to what neurotransmitter systems and brain regions are involved.
All drugs of abuse share the ability to elevate dopamine transmission, either directly
or indirectly (Hyman et al., 2006). It is therefore not surprising that dopamine and the
mesocorticolimbic “reward” circuitry have been a primary focus of neuroscience re-
search related to addiction. The most consistent findings to emerge from imaging
studies of addicted patients are decreased dopamine type 2/3 (D2/3) receptor binding
capacity, particularly in the striatum, and decreased activity in prefrontal cortical
(PFC) areas that normally provide “top-down” executive control over striatal activity
(Volkow et al., 1993; Wang et al., 2012a). Decreased striatal D2/3 receptor binding
has also been reliably associated with novelty-seeking and impulsivity in both human
and animal studies (Buckholtz et al., 2010; Dalley et al., 2011; Leyton et al., 2002;
Zald et al., 2008), as has increased dopaminergic activity in the striatum at baseline
and in response to various stimuli in rats (Hooks et al., 1991; Piazza et al., 1991).
Further, human studies have shown that, in addition to lower levels of functional ac-
tivity in PFC areas, impulsive individuals exhibit decreased functional connectivity
between the PFC and subcortical structures, including the amygdala and ventral
striatum (Davis et al., 2013; Schmaal et al., 2012). Fewer studies have investigated
the neurobiological basis of “cue-reactivity,” though existing evidence from both
humans and animals suggests increased mesolimbic dopaminergic activity in
cue-reactive individuals (Flagel et al., 2011; Jasinska et al., 2014). Thus, a simplified
picture has emerged that individuals predisposed toward addiction are character-
ized neurobiologically by relatively high dopaminergic activity, coupled with
decreased “top-down” cortical control.
3 GENETICS
Twin studies have yielded heritability estimates of 30–70% for addiction (Agrawal
and Lynskey, 2008). Most of the genetic influences on substance use appear to be
shared across different classes of substances (Kendler et al., 2008; Tsuang et al.,
1998). However, the most robust findings from candidate gene and from genome-
wide association studies (GWAS) have been specific to certain classes of drugs.
For example, polymorphisms affecting the function of the alcohol dehydrogenase

and aldehyde dehydrogenase are some of the oldest and most potent known genetic
risk/resilience factors for any psychiatric disorder, but these are genes that specifi-
cally affect alcohol metabolism and are therefore specifically related to alcohol use
disorders (Hurley and Edenberg, 2012). To our knowledge, the only other association
reliably and convincingly detected by both GWAS and candidate gene studies is that
of nicotine dependence with variants of nicotinic acetylcholine receptor (nAChR)
subunit genes (Bierut et al., 2008). Although genes affecting several other proteins
have been associated with addiction, including gamma-amino butyric acid (GABA)
receptors, opioid receptors, and cannabinoid receptors, these findings have been in-
consistent across studies and generally specific to one or a few substances (Hall et al.,
2013; Wang et al., 2012b). Even studies of genes involved in dopamine transmission
have yielded mixed results, despite the fact that augmentation of dopamine transmis-
sion in the ventral striatum is a mechanistic pathway common to all drugs of abuse
(Hyman et al., 2006). Difficulties in the replication of candidate gene findings do not
necessarily mean that the associations are invalid; instead, it may indicate that indi-
vidual genetic effects are limited to specific populations and endophenotypes. In-
deed, transgenic animal studies of candidate genes generally show much more
consistent and robust effects on drug-taking behaviors than human association stud-
ies would otherwise suggest. Thus, like most psychiatric disorders, addiction appears
to be highly heritable, but the multifactorial and polygenic nature of the disorder
makes specific gene associations very difficult to detect.
4 EPIGENETICS
Intriguingly, emerging evidence from the animal literature is implicating transge-
nerational epigenetic mechanisms as possible contributors to the heritability of ad-
dictive disorders (Vassoler and Sadri-Vakili, 2014; Yohn et al., 2015). Epigenetic
changes are experience-dependent chemical alterations to chromosomes that affect
gene expression. The most widely studied epigenetic markers are DNA methylation
and histone methylation and acetylation. Although there have been a number of stud-
ies demonstrating epigenetic modifications in response to drugs of abuse (for review,
see Renthal and Nestler, 2008), few, to our knowledge, have identified epigenetic
mechanisms that contribute to addiction vulnerability. Thus, for the purpose of this
chapter, we will focus on transgenerational epigenetic mechanisms, that is, those that
are retained throughout embryonic development, and thereby passed on from parent
to offspring. For example, exposure to alcohol causes several epigenetic changes to
be passed on to offspring and successive generations of rodents, including demeth-
ylation of the imprinted gene H19 (Ouko et al., 2009), demethylation of the promoter
region of exon IV of the brain-derived neurotrophic factor (Bdnf) gene (Finegersh
and Homanics, 2014), increased methylation of the dopamine transporter (Dat) pro-
moter (Kim et al., 2014), and methylation of the pro-opioid melanocortin (Pomc)
promoter in the arcuate nucleus (Govorko et al., 2012). Remarkably, there are a
5 Developmental factors 7
number of common associations of these epigenetic changes, including increased

Bdnf expression in the ventral tegmental area (VTA), decreased DAT in the cortex
and striatum, decreased hypothalamic Pomc (Govorko et al., 2012), decreased fear
behaviors, increased aggression and impulsivity (Meek et al., 2007), and attention
deficits (Kim et al., 2014).
There is also evidence of transgenerational epigenetic changes induced by other
substances. For example, rats exposed to opioids have progeny that exhibit altered re-
sponses to dopaminergic agents (Byrnes et al., 2013; Vyssotski, 2011). Offspring of
dams exposed to nicotine are hyperactive and inattentive, and have increased methyl-
ation of the Bdnf promoter and decreased BDNF levels in the frontal cortex (Toledo-
Rodriguez et al., 2010; Yochum et al., 2014; Zhu et al., 2014). In contrast to changes
induced by other substances, the transgenerational effects of cocaine exposure may
actually be protective, as the progeny of cocaine-exposed rodents have increased
acetylated histone 3 associated with Bdnf exon IV, increased BDNF expression in
the medial prefrontal cortex, and reduced cocaine self-administration (Vassoler
et al., 2013). Though many mechanistic details for these effects remain to be discov-
ered, and all of the epigenetic findings mentioned here await further confirmation from
other groups, transgenerational epigenetic inheritance of risk may prove to be an im-
portant component of individual differences in vulnerability to addiction.
5 DEVELOPMENTAL FACTORS
Environmental factors and life experiences also play a large role in determining an
individual’s risk for developing an addictive disorder. Several studies have shown
that the younger a person is upon first exposure to drugs or alcohol, the higher their
risk of addiction, even after controlling for other variables (e.g., Chen et al., 2009;
Dawson et al., 2008; King and Chassin, 2007). Similarly, animal studies have shown
that exposure to stress, particularly in the prenatal or early childhood period, in-
creases the risk of addiction (Deminiere et al., 1992; Henry et al., 1995; Kippin
et al., 2008). Human imaging studies show that the adolescent brain is also partic-
ularly responsive to stressful stimuli (Gunnar et al., 2009; Stroud et al., 2009).
Human and animal studies have shown that stress very early in life will sensitize
the hypothalamic-pituitary-adrenal axis, such that later stress responses become ex-
aggerated (Higley et al., 1991; Liu et al., 1997; Tarullo and Gunnar, 2006). In addi-
tion, dopaminergic activity increases in the striatum and decreases in cortical regions
after early life stress in both humans and animals (Blanc et al., 1980; Brake et al.,
2004; Pruessner et al., 2004). Importantly, animal studies indicate that many of these
changes can be mitigated by increased maternal care or environmental enrichment
(Barbazanges et al., 1996; Plotsky and Meaney, 1993; Solinas et al., 2010). Genetic
studies in humans have shown that childhood experiences moderate the effects of
several genes on addiction, including polymorphisms in the serotonin transporter,
dopamine type 2 receptor, monoamine oxidase, and corticotrophin releasing hor-
mone receptor 1 (Bau et al., 2000; Bjork et al., 2010; Blomeyer et al., 2008). Thus,
many genetic risk factors may only become relevant in the setting of known envi-
ronmental stressors such as parental divorce, migration, and comorbid psychiatric
illness; conversely, genetic influences may be reduced by protective environmental
factors such as marriage, religiosity, and parental involvement (Dick et al., 2007a,b;
Heath et al., 1989; Koopmans et al., 1999).
The contributions of genetic and environmental risk factors vary over the course
of development, and multiple lines of evidence from the human and animal literature
implicate adolescence as a critical period in the development of addictive disorders
(Adriani and Laviola, 2004; Belsky et al., 2013; Vrieze et al., 2012). As with most
psychiatric disorders, the onset of addictive disorders peaks in adolescence
(SAMSHA, 2014). Brain maturation takes place unevenly throughout the brain, with
basic motivational regions such as the striatum developing well before more cogni-
tive PFC regions that are involved in exerting control over appetitive urges (Dahl,
2008; Gogtay et al., 2004; Sowell et al., 2003). Dopaminergic activity throughout
the limbic system is increased during adolescence (McCutcheon et al., 2012;
Rosenberg and Lewis, 1994). In addition, glutamatergic connections between the
prefrontal cortex and subcortical structures, including the ventral striatum and amyg-
dala, are reduced in adolescents (Brenhouse et al., 2008; Cunningham et al., 2002).
Hence, the adolescent brain is sometimes described as a high-performance sports car
with faulty brakes. As might be expected based on these neurobiological character-
istics, adolescents are more impulsive and sensation-seeking than adults (Adriani and
Laviola, 2003; Adriani et al., 1998; Romer et al., 2009). They are also more likely to
engage in risky behaviors, including taking drugs more often and in larger quantities,
than adults (Merrick et al., 2004; SAMSHA, 2014; Steinberg, 2008).
It is interesting to note that risk-taking behavior may also serve important, adap-
tive functions for adolescents. The transition to independence requires stepping out-
side of one’s comfort zone in order to achieve a sense of competence in adult
situations. Risky activities such as substance use may contribute to social develop-
ment, as teens who experiment with drugs are more socially competent and accepted
by their peers than abstainers (Spear, 2000). Social aspects of the environment are
more emotionally salient for adolescents, and this sensitivity is reflected by increased
limbic activity in response to social cues (Choudhury et al., 2006; Monk et al., 2003;
Yang et al., 2003). Perhaps unsurprisingly, then, substance use and antisocial behav-
ior among peers is a strong risk factor for the development of addiction in adoles-
cence (Dick et al., 2007a,b; Harden et al., 2008). Hormonal influences are also
likely to play a role in addiction during this time period, as testosterone contributes
to synaptic pruning during adolescence (Nguyen et al., 2013). Women, though less
likely overall to develop addictive disorders, generally have a more severe and
treatment-resistant course of illness, more stress-related comorbidities, and faster
transitions to compulsive drug use than men, again highlighting the influence of hor-
mones on drug-taking behavior (Kuhn, 2015; Nguyen et al., 2013). These findings,
taken together, illustrate that adolescence is an extraordinarily sensitive time window
with regard to the development of addiction.
6 Conclusion and future directions 9
6 CONCLUSION AND FUTURE DIRECTIONS

The information garnered from research into addiction vulnerability has the potential
to inform and improve treatment of addictive disorders in several ways. For instance,
there is considerable interest in using biomarkers to identify individuals who are at
high risk of developing addiction. Theoretically, information about a person’s dopa-
minergic activity, functional connectivity patterns, or even BDNF expression pat-
terns in the brain could be used to estimate risk, but currently none of these
indicators are sensitive or specific enough to serve as true biomarkers. Genetic in-
formation has the potential to be very informative, as heredity can account for up-
ward of 70% of an individual’s risk for addiction. However, other than a handful
of substance-specific genes, genetic studies have so far not been very successful
at consistently finding particular genotypes that contribute to addiction liability. Be-
cause of the multifactorial nature of addiction, future genetic studies may need to
focus on particular subpopulations, endophenotypes, or subtypes of addiction, in ad-
dition to better accounting for environmental modifiers of genetic risk, in order to
identify clinically relevant risk alleles. Emerging evidence from the animal literature
suggests that epigenomic association studies may also be useful for accounting for
the heritable portion of addiction vulnerability.
However, despite gaps in our knowledge of the specific genes and neural circuitry
involved in addiction liability, existing information is often enough to produce clin-
ically relevant estimates of an individual’s risk of developing an addictive disorder.
For example, we already know that an impulsive, sensation-seeking individual,
whose parents and grandparents suffered from addiction, who undergoes neglect
or other trauma at an early age, and who is surrounded by peers engaging in high-
risk substance use, is very likely to develop an addictive disorder. We can even pre-
dict with considerable confidence that the disorder will emerge sometime between
the ages of 12 and 25. The question then becomes, how do we use this information to
improve clinical outcomes? First, do no harm. In 2013, the leading cause of acciden-
tal death in the United States was drug overdose, and over 50% of the drugs involved
were prescription opioids and benzodiazepines (CDC, 2014, 2015). Prescribing phy-
sicians should make a concerted effort to limit access to drugs with addictive poten-
tial for individuals and relatives of individuals at high risk of developing addictive
disorders, because the vast majority of abused prescription drugs are prescribed ei-
ther to the user themselves or to a relative of the user (SAMSHA, 2014). Patients
should be educated about their own risk profile and that of their family members,
so that they can make informed decisions about the way they use potentially addic-
tive substances. Formal prevention programs aimed at adolescents have largely
failed to influence substance use rates, but parental behaviors often have a profound
effect on teenage substance use (SAMSHA, 2014). Thus, parents of adolescents who
are at high risk of developing addiction should be encouraged to take steps that are
known to reduce the risk of addiction, such as explicitly discouraging drug use, mon-
itoring the child’s peers and activities, actively involving themselves in the child’s
Neural Epigenetic
plasticity factors DA genes
Transgenerational (e.g., DAT, COMT, Stress
genes MAOA, D1R, D2R) genes
(e.g., Synaptophysin,
(e.g., 5-HTR,
BDNF)
CRHR)
Ventral DA
PFC VTA
striatum
HPA axis
Stress
Novelty-seeking
Impulsivity cue-reactivity
Negative
environment
High-risk drug use Positive

environment
Drug-
response
genes Drug effects
(e.g., OPRM1, nAchR,
GABRA1, GABRA2, Peer use,
CB1R, ADH/ALDH) drug
availability
FIGURE 1
Addiction vulnerability at multiple, interacting levels. High-risk drug use (red; black in the
print version) is potentiated by personality traits (green; light gray in the print version)
including impulsivity, novelty-seeking, and cue-reactivity. These personality traits, in turn,
reflect neurobiological traits (yellow; white in the print version) including increased
dopaminergic activity and decreased prefrontal cortical control over ventral striatal impulses.
Addictive drugs (purple; dark gray in the print version) directly affect this neural circuitry,
which is one driver of the cycle of addiction. Stress (black), acting through the hypothalamic
pituitary adrenal (HPA) axis, predisposes toward addictive behavior by enhancing
dopaminergic activity. Environmental factors (gray) affect vulnerability either through their
effects on stress, or via a more direct effect on the probability of drug use. Genetic
polymorphisms (blue; light gray in the print version) affect this system in a variety of ways.
“Drug–response genes” modulate the pharmacologic effects of drug use, while other genes
modulate dopaminergic activity, stress reactivity, or corticolimbic connectivity patterns.
Transgenerational epigenetic influences (orange; dark gray in the print version) may be
mediated by these same gene families, with most of the evidence so far implicating
dopaminergic genes and synaptic plasticity genes. Definitions of connectors: arrows indicate
one variable potentiating the other; lines terminating with a hash bar indicate an inhibitory
relationship; lines terminating with a circle indicate a positive association; double-hashed
lines indicate a relationship that can be either positive or negative, depending on the allele.
Abbreviations: 5-HTR, serotonin receptor; ADH, alcohol dehydrogenase; ALDH, aldehyde
dehydrogenase; BDNF, brain-derived neurotrophic factor; CB1R, cannabinoid type 1
receptor; COMT, catechol-O-methyl transferase; CRHR, corticotrophin-releasing hormone
receptor; D1R, dopamine type 1 receptor; D2R, dopamine type 2 receptor; DAT, dopamine
transporter; GABRA1, gamma-aminobutyric acid (GABA) receptor subunit alpha-1;
GABRA2, GABA receptor subunit alpha-2; HPA, hypothalamic-pituitary-adrenal; MAOA,
monoamine oxidase A; nAChR, nicotinic acetylcholine receptor; OPRM1, opioid receptor mu
1; PFC, prefrontal cortex; VTA, ventral tegmental area.
References 11
homework and other activities, providing a stable family life, and involving the child
in religious activities.
Treatment of patients who already have addiction may also benefit from knowl-
edge of specific vulnerability factors. For example, personality traits associated with
addiction can, in some cases, be targeted by specific clinical interventions. To date,
few studies have taken this approach, but one indication of its potential utility is the
finding that, for individuals with addiction and comorbid attention deficit hyperac-
tivity disorder, treatment of their impulsivity with potentially addictive psychostimu-
lants paradoxically reduces their risk of relapse (Levin et al., 2007). Selective
serotonin reuptake inhibitors (SSRIs) have largely been disappointing as a treatment
for addiction (Nunes and Levin, 2004) but because they actually reduce the neurot-
icism trait (Tang et al., 2009), SSRIs might be useful in treating a subset of patients
for whom neuroticism is a primary driver of their addiction. Information about per-
sonality traits and other neurobiological factors might also be used to tailor specific
treatment interventions; for example, emphasizing stress reduction in individuals
with high neuroticism, or focusing more on identifying and avoiding cues for indi-
viduals with markers of excessive cue-reactivity. Sophisticated methods (e.g., opto-
genetics, designer receptors exclusively activated by designer drugs—DREADDs)
are being developed in rodents to directly manipulate the neural circuitry responsible
for individual differences in cue-reactivity and other behavioral traits, but because
many of these approaches involve genetic modification of neurons, they are many
years away from being available for clinical trials.
As research progresses, the multifactorial nature of addiction becomes even more
apparent. Yet, remarkably, as outlined above, there are a number of vulnerability fac-
tors that repeatedly appear in the literature, common to both human and animal stud-
ies, and linked at multiple levels of analysis (e.g., genetic and neurobiological; see
Fig. 1 for a simplified visual summary). Moving forward, the advent and accessibil-
ity of new technology (e.g., Saunders et al., 2015) will allow increasingly precise
analysis of the neurobiological factors contributing to addiction liability. For exam-
ple, chemogenetic approaches could be used to manipulate “top-down” cortical cir-
cuits in order to “switch” the behavioral phenotype of an animal from one that is
addiction-prone, to one that is addiction-resilient. A continuing challenge for the
field will be integrating this new knowledge with the other layers of genetic, epige-
netic, developmental, and environmental factors that interact in multiple ways with
this neural circuitry in order to determine an individual’s risk for addiction.
REFERENCES
Adriani, W., Laviola, G., 2003. Elevated levels of impulsivity and reduced place conditioning
with d-amphetamine: two behavioral features of adolescence in mice. Behav. Neurosci.
117 (4), 695–703.
Adriani, W., Laviola, G., 2004. Windows of vulnerability to psychopathology and therapeutic
strategy in the adolescent rodent model. Behav. Pharmacol. 15 (5-6), 341–352.
Adriani, W., Chiarotti, F., Laviola, G., 1998. Elevated novelty seeking and peculiar
d-amphetamine sensitization in periadolescent mice compared with adult mice. Behav.
Neurosci. 112 (5), 1152–1166.
Agrawal, A., Lynskey, M.T., 2008. Are there genetic influences on addiction: evidence from
family, adoption and twin studies. Addiction 103 (7), 1069–1081.
Anthony, J.C., Warner, S.A., Kessler, R.C., 1994. Comparative epidemiology of dependence
on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National
Comorbidity Survey. Exp. Clin. Psychopharmacol. 2 (3), 244–268.
Barbazanges, A., Vallee, M., Mayo, W., Day, J., Simon, H., Le Moal, M., Maccari, S., 1996.
Early and later adoptions have different long-term effects on male rat offspring.
J. Neurosci. 16 (23), 7783–7790.
Bau, C.H., Almeida, S., Hutz, M.H., 2000. The TaqI A1 allele of the dopamine D2 receptor
gene and alcoholism in Brazil: association and interaction with stress and harm avoidance
on severity prediction. Am. J. Med. Genet. 96 (3), 302–306.
Belin, D., Mar, A.C., Dalley, J.W., Robbins, T.W., Everitt, B.J., 2008. High impulsivity pre-
dicts the switch to compulsive cocaine-taking. Science 320 (5881), 1352–1355.
Belsky, D.W., Moffitt, T.E., Baker, T.B., Biddle, A.K., Evans, J.P., Harrington, H., et al.,
2013. Polygenic risk and the developmental progression to heavy, persistent smoking
and nicotine dependence: evidence from a 4-decade longitudinal study. JAMA Psychiatry
70 (5), 534–542.
Bierut, L.J., Stitzel, J.A., Wang, J.C., Hinrichs, A.L., Grucza, R.A., Xuei, X., et al., 2008. Var-
iants in nicotinic receptors and risk for nicotine dependence. Am. J. Psychiatry 165 (9),
1163–1171.
Bjork, K., Hansson, A.C., Sommer, W.H., 2010. Genetic variation and brain gene expression
in rodent models of alcoholism implications for medication development. Int. Rev. Neu-
robiol. 91, 129–171.
Blanc, G., Herve, D., Simon, H., Lisoprawski, A., Glowinski, J., Tassin, J.P., 1980. Response
to stress of mesocortico-frontal dopaminergic neurones in rats after long-term isolation.
Nature 284 (5753), 265–267.
Blomeyer, D., Treutlein, J., Esser, G., Schmidt, M.H., Schumann, G., Laucht, M., 2008. In-
teraction between CRHR1 gene and stressful life events predicts adolescent heavy alcohol
use. Biol. Psychiatry 63 (2), 146–151.
Bornovalova, M.A., Daughters, S.B., Hernandez, G.D., Richards, J.B., Lejuez, C.W., 2005.
Differences in impulsivity and risk-taking propensity between primary users of crack co-
caine and primary users of heroin in a residential substance-use program. Exp. Clin. Psy-
chopharmacol. 13 (4), 311–318.
Brake, W.G., Zhang, T.Y., Diorio, J., Meaney, M.J., Gratton, A., 2004. Influence of early post-
natal rearing conditions on mesocorticolimbic dopamine and behavioural responses to
psychostimulants and stressors in adult rats. Eur. J. Neurosci. 19 (7), 1863–1874.
Brenhouse, H.C., Sonntag, K.C., Andersen, S.L., 2008. Transient D1 dopamine receptor ex-
pression on prefrontal cortex projection neurons: relationship to enhanced motivational
salience of drug cues in adolescence. J. Neurosci. 28 (10), 2375–2382.
Buckholtz, J.W., Treadway, M.T., Cowan, R.L., Woodward, N.D., Li, R., Ansari, M.S., et al.,
2010. Dopaminergic network differences in human impulsivity. Science 329 (5991), 532.
Byrnes, J.J., Johnson, N.L., Carini, L.M., Byrnes, E.M., 2013. Multigenerational effects of ad-
olescent morphine exposure on dopamine D2 receptor function. Psychopharmacology
(Berl) 227 (2), 263–272.
References 13
Carter, B.L., Tiffany, S.T., 1999. Cue-reactivity and the future of addiction research.
Addiction 94 (3), 349–351.
CDC, 2014. Centers for Disease Control and Prevention. Web-based Injury Statistics Query
and Reporting System (WISQARS). http://www.cdc.gov/injury/wisqars/fatal.html.
CDC, 2015. Centers for Disease Control and Prevention. National Vital Statistics System Mor-
tality Data. http://www.cdc.gov/nchs/deaths.htm.
Chen, C.Y., Storr, C.L., Anthony, J.C., 2009. Early-onset drug use and risk for drug depen-
dence problems. Addict. Behav. 34 (3), 319–322.
Choudhury, S., Blakemore, S.J., Charman, T., 2006. Social cognitive development during ad-
olescence. Soc. Cogn. Affect. Neurosci. 1 (3), 165–174.
Cunningham, M.G., Bhattacharyya, S., Benes, F.M., 2002. Amygdalo-cortical sprouting con-
tinues into early adulthood: implications for the development of normal and abnormal
function during adolescence. J. Comp. Neurol. 453 (2), 116–130.
Dahl, R.E., 2008. Biological, developmental, and neurobehavioral factors relevant to adoles-
cent driving risks. Am. J. Prev. Med. 35 (3 Suppl.), S278–S284.
Dalley, J.W., Fryer, T.D., Brichard, L., Robinson, E.S., Theobald, D.E., Laane, K., et al., 2007.
Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement.
Science 315 (5816), 1267–1270.
Dalley, J.W., Everitt, B.J., Robbins, T.W., 2011. Impulsivity, compulsivity, and top-down
cognitive control. Neuron 69 (4), 680–694.
Davis, F.C., Knodt, A.R., Sporns, O., Lahey, B.B., Zald, D.H., Brigidi, B.D., Hariri, A.R.,
2013. Impulsivity and the modular organization of resting-state neural networks. Cereb.
Cortex 23 (6), 1444–1452.
Dawson, D.A., Goldstein, R.B., Chou, S.P., Ruan, W.J., Grant, B.F., 2008. Age at first drink
and the first incidence of adult-onset DSM-IV alcohol use disorders. Alcohol. Clin. Exp.
Res. 32 (12), 2149–2160.
Deminiere, J.M., Piazza, P.V., Guegan, G., Abrous, N., Maccari, S., Le Moal, M., Simon, H.,
1992. Increased locomotor response to novelty and propensity to intravenous amphet-
amine self-administration in adult offspring of stressed mothers. Brain Res. 586 (1),
135–139.
Deroche-Gamonet, V., Belin, D., Piazza, P.V., 2004. Evidence for addiction-like behavior in
the rat. Science 305 (5686), 1014–1017.
Dick, D.M., Pagan, J.L., Holliday, C., Viken, R., Pulkkinen, L., Kaprio, J., Rose, R.J., 2007a.
Gender differences in friends’ influences on adolescent drinking: a genetic epidemiolog-
ical study. Alcohol. Clin. Exp. Res. 31 (12), 2012–2019.
Dick, D.M., Viken, R., Purcell, S., Kaprio, J., Pulkkinen, L., Rose, R.J., 2007b. Parental mon-
itoring moderates the importance of genetic and environmental influences on adolescent
smoking. J. Abnorm. Psychol. 116 (1), 213–218.
Dick, D.M., Aliev, F., Latendresse, S.J., Hickman, M., Heron, J., Macleod, J., et al., 2013. Ad-
olescent alcohol use is predicted by childhood temperament factors before age 5, with me-
diation through personality and peers. Alcohol. Clin. Exp. Res. 37 (12), 2108–2117.
Ersche, K.D., Turton, A.J., Chamberlain, S.R., Muller, U., Bullmore, E.T., Robbins, T.W.,
2012. Cognitive dysfunction and anxious-impulsive personality traits are endophenotypes
for drug dependence. Am. J. Psychiatry 169 (9), 926–936.
Ersche, K.D., Jones, P.S., Williams, G.B., Smith, D.G., Bullmore, E.T., Robbins, T.W., 2013.
Distinctive personality traits and neural correlates associated with stimulant drug use ver-
sus familial risk of stimulant dependence. Biol. Psychiatry 74 (2), 137–144.
Finegersh, A., Homanics, G.E., 2014. Paternal alcohol exposure reduces alcohol drinking and
increases behavioral sensitivity to alcohol selectively in male offspring. PLoS One 9 (6),
e99078.
Flagel, S.B., Clark, J.J., Robinson, T.E., Mayo, L., Czuj, A., Willuhn, I., et al., 2011.
A selective role for dopamine in stimulus-reward learning. Nature 469 (7328), 53–57.
Gogtay, N., Giedd, J.N., Lusk, L., Hayashi, K.M., Greenstein, D., Vaituzis, A.C., et al., 2004.
Dynamic mapping of human cortical development during childhood through early adult-
hood. Proc. Natl. Acad. Sci. U. S. A. 101 (21), 8174–8179.
Govorko, D., Bekdash, R.A., Zhang, C., Sarkar, D.K., 2012. Male germline transmits fetal al-
cohol adverse effect on hypothalamic proopiomelanocortin gene across generations. Biol.
Psychiatry 72 (5), 378–388.
Gunnar, M.R., Wewerka, S., Frenn, K., Long, J.D., Griggs, C., 2009. Developmental changes
in hypothalamus-pituitary-adrenal activity over the transition to adolescence: normative
changes and associations with puberty. Dev. Psychopathol. 21 (1), 69–85.
Hall, F.S., Drgonova, J., Jain, S., Uhl, G.R., 2013. Implications of genome wide association
studies for addiction: are our a priori assumptions all wrong? Pharmacol. Ther. 140 (3),
267–279.
Harden, K.P., Hill, J.E., Turkheimer, E., Emery, R.E., 2008. Gene-environment correlation
and interaction in peer effects on adolescent alcohol and tobacco use. Behav. Genet.
38 (4), 339–347.
Heath, A.C., Jardine, R., Martin, N.G., 1989. Interactive effects of genotype and social envi-
ronment on alcohol consumption in female twins. J. Stud. Alcohol 50 (1), 38–48.
Henry, C., Guegant, G., Cador, M., Arnauld, E., Arsaut, J., Le Moal, M., Demotes-Mainard, J.,
1995. Prenatal stress in rats facilitates amphetamine-induced sensitization and induces
long-lasting changes in dopamine receptors in the nucleus accumbens. Brain Res.
685 (1–2), 179–186.
Hicks, B.M., Foster, K.T., Iacono, W.G., McGue, M., 2013. Genetic and environmental influ-
ences on the familial transmission of externalizing disorders in adoptive and twin off-
spring. JAMA Psychiatry 70 (10), 1076–1083.
Higley, J.D., Hasert, M.F., Suomi, S.J., Linnoila, M., 1991. Nonhuman primate model of al-
cohol abuse: effects of early experience, personality, and stress on alcohol consumption.
Proc. Natl. Acad. Sci. U. S. A. 88 (16), 7261–7265.
Hooks, M.S., Jones, G.H., Smith, A.D., Neill, D.B., Justice Jr., J.B., 1991. Response to novelty
predicts the locomotor and nucleus accumbens dopamine response to cocaine. Synapse
9 (2), 121–128.
Hurley, T.D., Edenberg, H.J., 2012. Genes encoding enzymes involved in ethanol metabolism.
Alcohol Res. 34 (3), 339–344.
Hyman, S.E., Malenka, R.C., Nestler, E.J., 2006. Neural mechanisms of addiction: the role of
reward-related learning and memory. Annu. Rev. Neurosci. 29, 565–598.
Janes, A.C., Pizzagalli, D.A., Richardt, S., deB Frederick, B., Chuzi, S., Pachas, G., et al.,
2010. Brain reactivity to smoking cues prior to smoking cessation predicts ability to main-
tain tobacco abstinence. Biol. Psychiatry 67 (8), 722–729.
Jasinska, A.J., Stein, E.A., Kaiser, J., Naumer, M.J., Yalachkov, Y., 2014. Factors modulating
neural reactivity to drug cues in addiction: a survey of human neuroimaging studies. Neu-
rosci. Biobehav. Rev. 38, 1–16.
Kendler, K.S., Schmitt, E., Aggen, S.H., Prescott, C.A., 2008. Genetic and environmental in-
fluences on alcohol, caffeine, cannabis, and nicotine use from early adolescence to middle
adulthood. Arch. Gen. Psychiatry 65 (6), 674–682.
References 15
Kim, P., Choi, C.S., Park, J.H., Joo, S.H., Kim, S.Y., Ko, H.M., et al., 2014. Chronic exposure
to ethanol of male mice before mating produces attention deficit hyperactivity disorder-
like phenotype along with epigenetic dysregulation of dopamine transporter expression
in mouse offspring. J. Neurosci. Res. 92 (5), 658–670.
King, K.M., Chassin, L., 2007. A prospective study of the effects of age of initiation of alcohol
and drug use on young adult substance dependence. J. Stud. Alcohol Drugs 68 (2), 256–265.
Kippin, T.E., Szumlinski, K.K., Kapasova, Z., Rezner, B., See, R.E., 2008. Prenatal stress
enhances responsiveness to cocaine. Neuropsychopharmacology 33 (4), 769–782.
Koopmans, J.R., Slutske, W.S., van Baal, G.C., Boomsma, D.I., 1999. The influence of reli-
gion on alcohol use initiation: evidence for genotype X environment interaction. Behav.
Genet. 29 (6), 445–453.
Kotov, R., Gamez, W., Schmidt, F., Watson, D., 2010. Linking "big" personality traits to anx-
iety, depressive, and substance use disorders: a meta-analysis. Psychol. Bull. 136 (5),
768–821.
Kuhn, C., 2015. Emergence of sex differences in the development of substance use and abuse
during adolescence. Pharmacol. Ther. 153, 55–78.
Lejuez, C.W., Bornovalova, M.A., Daughters, S.B., Curtin, J.J., 2005. Differences in impul-
sivity and sexual risk behavior among inner-city crack/cocaine users and heroin users.
Drug Alcohol Depend. 77 (2), 169–175.
Lejuez, C.W., Paulson, A., Daughters, S.B., Bornovalova, M.A., Zvolensky, M.J., 2006. The
association between heroin use and anxiety sensitivity among inner-city individuals in res-
idential drug use treatment. Behav. Res. Ther. 44 (5), 667–677.
Levin, F.R., Evans, S.M., Brooks, D.J., Garawi, F., 2007. Treatment of cocaine dependent
treatment seekers with adult ADHD: double-blind comparison of methylphenidate and
placebo. Drug Alcohol Depend. 87 (1), 20–29.
Leyton, M., Boileau, I., Benkelfat, C., Diksic, M., Baker, G., Dagher, A., 2002. Amphetamine-
induced increases in extracellular dopamine, drug wanting, and novelty seeking: a PET/
[11C]raclopride study in healthy men. Neuropsychopharmacology 27 (6), 1027–1035.
Liu, D., Diorio, J., Tannenbaum, B., Caldji, C., Francis, D., Freedman, A., et al., 1997. Ma-
ternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal re-
sponses to stress. Science 277 (5332), 1659–1662.
McCutcheon, J.E., Conrad, K.L., Carr, S.B., Ford, K.A., McGehee, D.S., Marinelli, M., 2012.
Dopamine neurons in the ventral tegmental area fire faster in adolescent rats than in adults.
J. Neurophysiol. 108 (6), 1620–1630.
Meek, L.R., Myren, K., Sturm, J., Burau, D., 2007. Acute paternal alcohol use affects offspring
development and adult behavior. Physiol. Behav. 91 (1), 154–160.
Merrick, J., Kandel, I., Birnbaum, L., Hyam, E., Press, J., Morad, M., 2004. Adolescent injury
risk behavior. Int. J. Adolesc. Med. Health 16 (3), 207–213.
Monk, C.S., McClure, E.B., Nelson, E.E., Zarahn, E., Bilder, R.M., Leibenluft, E., et al., 2003.
Adolescent immaturity in attention-related brain engagement to emotional facial expres-
sions. Neuroimage 20 (1), 420–428.
Nguyen, T.V., McCracken, J., Ducharme, S., Botteron, K.N., Mahabir, M., Johnson, W., et al.,
2013. Testosterone-related cortical maturation across childhood and adolescence. Cereb.
Cortex 23 (6), 1424–1432.
Nunes, E.V., Levin, F.R., 2004. Treatment of depression in patients with alcohol or other drug
dependence: a meta-analysis. JAMA 291 (15), 1887–1896.
Ouko, L.A., Shantikumar, K., Knezovich, J., Haycock, P., Schnugh, D.J., Ramsay, M., 2009.
Effect of alcohol consumption on CpG methylation in the differentially methylated regions
of H19 and IG-DMR in male gametes: implications for fetal alcohol spectrum disorders.
Alcohol. Clin. Exp. Res. 33 (9), 1615–1627.
Piazza, P.V., Deminiere, J.M., Le Moal, M., Simon, H., 1989. Factors that predict individual
vulnerability to amphetamine self-administration. Science 245 (4925), 1511–1513.
Piazza, P.V., Rouge-Pont, F., Deminiere, J.M., Kharoubi, M., Le Moal, M., Simon, H., 1991.
Dopaminergic activity is reduced in the prefrontal cortex and increased in the nucleus
accumbens of rats predisposed to develop amphetamine self-administration. Brain Res.
567 (1), 169–174.
Pingault, J.B., Cote, S.M., Galera, C., Genolini, C., Falissard, B., Vitaro, F., Tremblay, R.E.,
2013. Childhood trajectories of inattention, hyperactivity and oppositional behaviors and
prediction of substance abuse/dependence: a 15-year longitudinal population-based study.
Mol. Psychiatry 18 (7), 806–812.
Plotsky, P.M., Meaney, M.J., 1993. Early, postnatal experience alters hypothalamic
corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-
induced release in adult rats. Brain Res. Mol. Brain Res. 18 (3), 195–200.
Pruessner, J.C., Champagne, F., Meaney, M.J., Dagher, A., 2004. Dopamine release in
response to a psychological stress in humans and its relationship to early life maternal care:
a positron emission tomography study using [11C]raclopride. J. Neurosci. 24 (11),
2825–2831.
Renthal, W., Nestler, E.J., 2008. Epigenetic mechanisms in drug addiction. Trends Mol. Med.
14 (8), 341–350.
Rohsenow, D.J., Niaura, R.S., Childress, A.R., Abrams, D.B., Monti, P.M., 1990. Cue
reactivity in addictive behaviors: theoretical and treatment implications. Int. J. Addict.
25 (7A–8A), 957–993.
Romer, D., Betancourt, L., Giannetta, J.M., Brodsky, N.L., Farah, M., Hurt, H., 2009. Exec-
utive cognitive functions and impulsivity as correlates of risk taking and problem behavior
in preadolescents. Neuropsychologia 47 (13), 2916–2926.
Rosenberg, D.R., Lewis, D.A., 1994. Changes in the dopaminergic innervation of monkey pre-
frontal cortex during late postnatal development: a tyrosine hydroxylase immunohisto-
chemical study. Biol. Psychiatry 36 (4), 272–277.
SAMSHA, 2014. Results from the 2013 National Survey on Drug Use and Health: Summary of
National Findings. Substance Abuse and Mental Health Services Administration,
Rockville, MD.
Saunders, B.T., Robinson, T.E., 2010. A cocaine cue acts as an incentive stimulus in some but
not others: implications for addiction. Biol. Psychiatry 67 (8), 730–736.
Saunders, B.T., Robinson, T.E., 2011. Individual variation in the motivational properties of
cocaine. Neuropsychopharmacology 36 (8), 1668–1676.
Saunders, B.T., Richard, J.M., Janak, P.H., 2015. Contemporary approaches to neural circuit
manipulation and mapping: focus on reward and addiction. Philos. Trans. R. Soc. Lond.
B Biol. Sci. 370 (1677).
Schmaal, L., Goudriaan, A.E., van der Meer, J., van den Brink, W., Veltman, D.J., 2012.
The association between cingulate cortex glutamate concentration and delay discounting
is mediated by resting state functional connectivity. Brain Behav. 2 (5), 553–562.
Solinas, M., Thiriet, N., Chauvet, C., Jaber, M., 2010. Prevention and treatment of drug
addiction by environmental enrichment. Prog. Neurobiol. 92 (4), 572–592.
Sowell, E.R., Peterson, B.S., Thompson, P.M., Welcome, S.E., Henkenius, A.L., Toga, A.W.,
2003. Mapping cortical change across the human life span. Nat. Neurosci. 6 (3), 309–315.
References 17
Spear, L.P., 2000. The adolescent brain and age-related behavioral manifestations. Neurosci.
Biobehav. Rev. 24 (4), 417–463.
Steinberg, L., 2008. A social neuroscience perspective on adolescent risk-taking. Dev. Rev.
28 (1), 78–106.
Stroud, L.R., Foster, E., Papandonatos, G.D., Handwerger, K., Granger, D.A., Kivlighan, K.T.,
Niaura, R., 2009. Stress response and the adolescent transition: performance versus peer
rejection stressors. Dev. Psychopathol. 21 (1), 47–68.
Tang, T.Z., DeRubeis, R.J., Hollon, S.D., Amsterdam, J., Shelton, R., Schalet, B., 2009.
Personality change during depression treatment: a placebo-controlled trial. Arch. Gen.
Psychiatry 66 (12), 1322–1330.
Tarullo, A.R., Gunnar, M.R., 2006. Child maltreatment and the developing HPA axis. Horm.
Behav. 50 (4), 632–639.
Terracciano, A., Lockenhoff, C.E., Crum, R.M., Bienvenu, O.J., Costa Jr., P.T., 2008. Five-
Factor Model personality profiles of drug users. BMC Psychiatry 8, 22.
Toledo-Rodriguez, M., Lotfipour, S., Leonard, G., Perron, M., Richer, L., Veillette, S., et al.,
2010. Maternal smoking during pregnancy is associated with epigenetic modifications of
the brain-derived neurotrophic factor-6 exon in adolescent offspring. Am. J. Med. Genet.
B Neuropsychiatr. Genet. 153B (7), 1350–1354.
Tsuang, M.T., Lyons, M.J., Meyer, J.M., Doyle, T., Eisen, S.A., Goldberg, J., et al., 1998. Co-
occurrence of abuse of different drugs in men: the role of drug-specific and shared vulner-
abilities. Arch. Gen. Psychiatry 55 (11), 967–972.
Vassoler, F.M., Sadri-Vakili, G., 2014. Mechanisms of transgenerational inheritance of
addictive-like behaviors. Neuroscience 264, 198–206.
Vassoler, F.M., White, S.L., Schmidt, H.D., Sadri-Vakili, G., Pierce, R.C., 2013. Epigenetic
inheritance of a cocaine-resistance phenotype. Nat. Neurosci. 16 (1), 42–47.
Verdejo-Garcia, A., Lawrence, A.J., Clark, L., 2008. Impulsivity as a vulnerability marker for
substance-use disorders: review of findings from high-risk research, problem gamblers and
genetic association studies. Neurosci. Biobehav. Rev. 32 (4), 777–810.
Volkow, N.D., Fowler, J.S., Wang, G.J., Hitzemann, R., Logan, J., Schlyer, D.J., et al., 1993.
Decreased dopamine D2 receptor availability is associated with reduced frontal metabo-
lism in cocaine abusers. Synapse 14 (2), 169–177.
Vrieze, S.I., McGue, M., Iacono, W.G., 2012. The interplay of genes and adolescent
development in substance use disorders: leveraging findings from GWAS meta-analyses
to test developmental hypotheses about nicotine consumption. Hum. Genet. 131 (6),
791–801.
Vyssotski, D.L., 2011. Transgenerational epigenetic compensation. Evolocus 1, 1–6.
Wang, G.J., Smith, L., Volkow, N.D., Telang, F., Logan, J., Tomasi, D., et al., 2012a. De-
creased dopamine activity predicts relapse in methamphetamine abusers. Mol. Psychiatry
17 (9), 918–925.
Wang, J.C., Kapoor, M., Goate, A.M., 2012b. The genetics of substance dependence. Annu.
Rev. Genomics Hum. Genet. 13, 241–261.
Yang, T.T., Menon, V., Reid, A.J., Gotlib, I.H., Reiss, A.L., 2003. Amygdalar activation as-
sociated with happy facial expressions in adolescents: a 3-T functional MRI study. J. Am.
Acad. Child Adolesc. Psychiatry 42 (8), 979–985.
Yochum, C., Doherty-Lyon, S., Hoffman, C., Hossain, M.M., Zelikoff, J.T., Richardson, J.R.,
2014. Prenatal cigarette smoke exposure causes hyperactivity and aggressive behavior:
role of altered catecholamines and BDNF. Exp. Neurol. 254, 145–152.
Yohn, N.L., Bartolomei, M.S., Blendy, J.A., 2015. Multigenerational and transgenerational
inheritance of drug exposure: The effects of alcohol, opiates, cocaine, marijuana, and nic-
otine. Prog. Biophys. Mol. Biol. 118 (1-2), 21–33.
Zald, D.H., Cowan, R.L., Riccardi, P., Baldwin, R.M., Ansari, M.S., Li, R., et al., 2008. Mid-
brain dopamine receptor availability is inversely associated with novelty-seeking traits in
humans. J. Neurosci. 28 (53), 14372–14378.
Zhu, J., Lee, K.P., Spencer, T.J., Biederman, J., Bhide, P.G., 2014. Transgenerational trans-
mission of hyperactivity in a mouse model of ADHD. J. Neurosci. 34 (8), 2768–2773.
CHAPTER
Drug-induced neurotoxicity
in addiction medicine: From
prevention to harm reduction
S. Mohammad Ahmadi Soleimani*,†, Hamed Ekhtiari*,{,}, Jean Lud Cadet},1
2
*Neurocognitive Laboratory, Iranian National Center for Addiction Studies (INCAS), Tehran
University of Medical Sciences, Tehran, Iran
†
Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
{
Translational Neuroscience Program, Institute for Cognitive Science Studies (ICSS), Tehran, Iran
}
Research Center for Molecular and Cellular Imaging (RCMCI), Tehran University of Medical
}
Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program,
National Institutes of Health, Baltimore, MD, USA
1
Corresponing author: e-mail address: [email protected]
Abstract
Neurotoxicity is considered as a major cause of neurodegenerative disorders. Most drugs of
abuse have nonnegligible neurotoxic effects many of which are primarily mediated by several
dopaminergic and glutamatergic neurotransmitter systems. Although many researchers have
investigated the medical and cognitive consequences of drug abuse, the neurotoxicity induced
by these drugs still requires comprehensive attention. The science of neurotoxicity promises to
improve preventive and therapeutic strategies for brain disorders such as Alzheimer disease
and Parkinson’s disease. However, its clinical applications for addiction medicine remain
to be defined adequately. This chapter reviews the most commonly discussed mechanisms un-
derlying neurotoxicity induced by common drugs of abuse including amphetamines, cocaine,
opiates, and alcohol. In addition, the known factors that trigger and/or predispose to drug-
induced neurotoxicity are discussed. These factors include drug-related, individual-related,
and environmental insults. Moreover, we introduce some of the potential pharmacological
antineurotoxic interventions deduced from experimental animal studies. These interventions
involve various targets such as dopaminergic system, mitochondria, cell death signaling, and
NMDA receptors, among others. We conclude the chapter with a discussion of addicted pa-
tients who might benefit from such interventions.
Keywords
Neurotoxicity, Drugs of abuse, Neuroprotection, Addiction medicine

19
20 CHAPTER 2 Drug-induced neurotoxicity in addiction medicine
1 INTRODUCTION
Neurotoxicity is defined as any adverse effect on the structure or function of the cen-
tral and peripheral nervous systems at the result of a diversity of biological, chemical,
or physical agents. Based on the location or the severity of neurotoxic damages, these
can be accompanied by neurocognitive deficits that impact various aspects of daily
life activities. Although neurotoxicity is a well-known contributory factor in some
neurodegenerative including Alzheimer’s disease and Parkinson’s disease, the im-
pact of drug-induced damage in addicted patients remains to be fully evaluated. Nev-
ertheless, the accumulated evidence suggests that drug-induced neurotoxicity is
mediated by activation of several neurotransmitter systems including dopamine
and glutamate that work in concert to damage the brain (Cadet et al., 2014). These
drug-induced damages can negatively impact various neurocognitive spheres that in-
clude memory, attention, decision-making, and executive functions (Cadet and
Bisagno, 2014). There is, at present, a burgeoning literature on the influence of these
cognitive deficits on social and psychological functioning. Nevertheless, much re-
mains to be done to provide a detailed hypothesis that might provide a link between
these drug-induced brain changes and treatment responses. Here, we provide a brief
review of the existing literature on the mechanisms of neurotoxicity consequent to
commonly abused drugs (amphetamines, cocaine, opiates, and alcohol). The chapter
also discusses identified predisposing factors, potentials for preventive, and thera-
peutic approaches, as well as future challenges to apply basic science knowledge
of drug-induced neurotoxic damage to clinical practice.
2 DRUG-INDUCED NEUROTOXICITY: MECHANISMS AND

PATHWAYS
During the past three decades, the efforts of several groups of investigators have led
to the identification of several cellular and molecular mechanisms of drug neurotox-
icity. This chapter presents the bases of toxicity produced by amphetamine, amphet-
amine derivatives, cocaine, and opiates.
2.1 OXIDATIVE STRESS

The increase in extracellular monoamines caused by drugs of abuse is thought to be
responsible for their addictive properties. Importantly, however, the increased dopa-
mine (DA) in the synaptic cleft might also be responsible for the neurotoxic damage
caused by several of these agents (Cadet and Brannock, 1998; Cadet et al., 2007).
In fact, this might provide a partial explanation for the original report of
methamphetamine-induced toxicity in brain regions with high monoaminergic content
(Gibb and Kogan, 1979). Dopamine by itself is neurotoxic both in vitro and in vivo
(Graham et al., 1978). It is easily oxidized via enzymatic and nonenzymatic mecha-
nisms and then induces oxidative stress (Cadet and Brannock, 1998). Amphetamine,
2 Drug-Induced neurotoxicity: Mechanisms and pathways 21
amphetamine derivatives, cocaine, 3,4-methylenedioxy-methamphetamine (MDMA),

and opiates have all been reported to produce oxidative stress within the nervous
system (Yamamoto and Bankson, 2005). Active metabolites of dopamine and/or
related substances might cause oxidative stress by forming free radicals via the for-
mation of quinones and the generation of quinone cascades secondary to MDMA
metabolism (Lyles and Cadet, 2003). Cocaine exposure causes oxidative stress by
increasing H2O2 concentration and decreasing catalase activity in rat prefrontal
cortex and striatum (Dietrich et al., 2005; Macêdo et al., 2005). Cocaine also causes
decreased levels of antioxidants such as glutathione (GSH) or vitamin E (Lipton
et al., 2003; Poon et al., 2007). In contrast to the situation for the psychostimulants,
much less is known about opiate-induced oxidative stress. However, heroin has
been reported to decrease the activities of superoxide dismutase (SOD), catalase,
and glutathione peroxidase (GPx) in the mouse brain. Heroin exposure is reported
to increase oxidative DNA damage, protein oxidation, and lipid peroxidation
(Qiusheng et al., 2005; Xu et al., 2006). Finally, morphine was shown to reduce
fatty acid contents in spinal cord and brain by causing oxidative stress (Ozmen
et al., 2007).
2.2 APOPTOTIC PROCESSES

There is convincing evidence that some drugs of abuse can cause neuronal apoptotic
cell death. Cells undergoing apoptosis are characterized by morphological and bio-
chemical hallmarks that include cell shrinkage, chromatin condensation, and frag-
mentation into membrane-bound apoptotic bodies. Cell death is triggered by
intrinsic and extrinsic molecular pathways that include increased permeability of mi-
tochondrial membrane and activation of death receptors ( Jayanthi et al., 2005).
Death pathways also involve activation of cysteine aspartic proteases (caspases)
and caspase-independent pathways (Kroemer and Martin, 2005). Experiments pub-
lished in the Cadet laboratory were among the first ones to show that amphetamine
and amphetamine derivatives could induce apoptosis in vitro and in vivo models
(Cadet et al., 2007). These observations have been extensively replicated (Cunha-
Oliveira et al., 2006; Dietrich et al., 2005; Oliveira et al., 2002). Amphetamine ex-
posure leads to caspase activation in various brain regions (Cunha-Oliveira et al.,
2006; Krasnova et al., 2005; Waren et al., 2007). Amphetamine exposure stimulates
mitochondrial pathways that lead to caspase activation. Mitochondria-dependent
death pathways involve the release of cytochrome c, decrease in mitochondrial po-
tential, and increased Bax/Bcl2 ratios (Imam et al., 2005; Krasnova et al., 2005;
Oliveira et al., 2003). Other studies have identified p53 as an important regulator
of D-amphetamine-induced cell death (Krasnova et al., 2005). MDMA can also in-
duce apoptosis in rat cortical neurons by activation of 5-HT2A receptors (Capela
et al., 2006). Exposure to cocaine can also activates biochemical mechanisms in-
volved in apoptosis without leading to morphological apoptotic characteristics
(Cunha-Oliveira et al., 2006; Dey et al., 2007; Imam et al., 2005; Mitchell and
Snyder-Keller, 2003; Oliveira et al., 2003). Interestingly, cocaine produces apoptosis
in human neuronal progenitor cells by generating oxidative stress (Poon et al., 2007).
Opiates may also cause apoptosis in humans and in animal models (Cunha-Oliveira
et al., 2007; Hu et al., 2002; Mao et al., 2002; Tramullas et al., 2008). Heroin and
morphine cause caspase activation and cytochrome c release from mitochondria
(Cunha-Oliveira et al., 2007; Oliveira et al., 2003) as well as increased Bax/Bcl2
ratios (Cunha-Oliveira et al., 2007; Mao et al., 2002). Chronic heroin exposure upre-
gulates proapoptotic proteins (Fas, FasL, and Bad) in the cortex and hippocampus of
mice (Tramullas et al., 2008). Morphological hallmarks of apoptosis have also been
observed in vitro following exposure to heroin (Cunha-Oliveira et al., 2007; Oliveira
et al., 2002).
2.3 EXCITOTOXICITY
Excitotoxicity refers to cell death due to the toxic effects of excitatory amino acids.
This happens at the result of massive Ca2+ influx secondary to the overactivation of
N-methyl-D-aspartate (NMDA) glutamate receptors. Methamphetamine induces
excitotoxicity by glutamate release and activation of glutamate receptors
(Yamamoto and Bankson, 2005). Administration of glutamate receptor antagonists
including MK-801 or dizocilpine reduces methamphetamine-induced neurodegen-
eration in different parts of the brain (Battaglia et al., 2002; Bowyer et al., 2001;
Chipana et al., 2008; Fuller et al., 1992; Gołembiowska et al., 2003; Ohmori
et al., 1993; Sonsalla et al., 1989; Weihmuller et al., 1992). The neurotoxic effects
of opiates may also be mediated by activation of NMDA receptors (Mao et al.,
2002). Crack abuse may also lead to excitotoxic damage (Oliveira et al., 2011).
Amphetamine (Reid et al., 1997; Wolf et al., 2000) and cocaine (Williams and
Steketee, 2004) both increase extracellular glutamate concentrations in the nucleus
accumbens, ventral tegmental area (VTA), striatum, and prefrontal cortex. In addi-
tion, long-term cocaine exposure also influences glutamate functions in the VTA and
nucleus accumbens. These alterations include changes in synaptic plasticity (i.e.,
increasing the number of dendritic spines), changes in glutamate homeostasis, and
activation of postsynaptic glutamatergic signaling (Uys and Reissner, 2011). In
addition, cocaine increases intracellular Ca2+ concentration in rat cortical neurons
(Cunha-Oliveira et al., 2010). This leads to the activation of several Ca2+-dependent
enzymes that cause degradation of proteins, phospholipids, and nucleic acids (Rego
and Oliveira, 2003). The adverse effects of alcohol may also involve hyperexcitabil-
ity during the process of alcohol withdrawal. This increase in glutamatergic trans-
mission may result from a combination of changes including increased NMDA
receptor activation, decreased GABA receptor activation, and enhanced function
of voltage-activated calcium channels (Dolin et al., 1987; Koppi et al., 1987;
Little et al., 1986; Lovinger, 1993; Skattebol and Rabin, 1987). Another important
aspect of alcohol withdrawal is thiamine deficiency (Martin et al., 1991). This vita-
min acts as a cofactor in several enzymatic reactions. In animal models, severe thi-
amine deficiency causes neurological symptoms such as convulsions. There is also
2 Drug-Induced neurotoxicity: Mechanisms and pathways 23
evidence supporting the link between excitotoxicity and thiamine deficiency

(Langlais and Mair, 1990). Specifically, thiamine deficiency-induced neuronal loss
and convulsions are diminished by the administration of the NMDA receptor antag-
onist, MK-801, in experimental animals.
2.4 INVOLVEMENT OF OTHER BIOCHEMICAL MECHANISMS

In addition to the mentioned mechanisms, other biochemical pathways may also
serve as triggers of drug-induced neurotoxicity. For example, activation of microglia
can lead to the release of proinflammatory mediators that may compromise neuronal
viability (Domercq and Matute, 2004). In the case of drug toxicity, methamphet-
amine exposure leads to microglial activation that appears in conjunction with do-
paminergic toxicity in the dorsal striatum (Bowyer et al., 1994; Escubedo et al.,
1998; Guilarte et al., 2003; Thomas and Kuhn, 2005; Thomas et al., 2004a,b). Im-
portantly, the time course of methamphetamine-induced microglial activation ap-
pears to coincide or to precede methamphetamine toxicity, supporting the notion
of the involvement of microglial cells in methamphetamine toxicity (Thomas
et al., 2004b). Of clinical relevance is the fact human methamphetamine addicts
show widespread microglial activation in their brains (Sekine et al., 2008).
Hyperthermia is another proposed mechanism for methamphetamine neurotoxic-
ity both in humans (Kalant and Kalant, 1975) and rodents (Sandoval et al., 2000).
Hyperthermia may potentiate drug-induced dopamine and tyrosine hydroxylase de-
pletion by increasing oxidative stress (Lin et al., 1991; Omar et al., 1987). In general,
biochemical reactions are sensitive to temperature changes including those occurring
in the brain. An additional organelle that is involved in methamphetamine toxicity is
the endoplasmic reticulum (ER) ( Jayanthi et al., 2004, 2009). Methamphetamine-
induced ER stress is thought to be the earliest factor leading to apoptosis in the mouse
brain after drug administration. Specifically, methamphetamine has been shown to
cause neuronal apoptosis through cross talks between ER and mitochondria-mediated
death cascades. This cross talk triggers both caspase-dependent and -independent
death pathways ( Jayanthi et al., 2004) and appears to depend on activation of DA
D1 receptors ( Jayanthi et al., 2009).
In the case of cocaine, administration of the drug produces increased synaptic
serotonin levels and changes in serotonin transporters (Cunningham et al., 1992;
Levy et al., 1994). Increased brain concentrations of serotonin can disrupt the
blood–brain barrier (BBB) (Sharma et al., 1990) and can cause hyperthermia
(Capela et al., 2009; Sharma, 2007). These findings are consistent with reports of
psychostimulant-induced hyperthermia (Hawkins and Davis, 2005; Hawkins
et al., 2004; Kousik et al., 2011; Lin et al., 1992; Monks et al., 2004; Sharma and
Ali, 2008). The issue of hyperthermia as adverse consequences of drug abuse is
of clinical relevance because they can impact the clinical course of patients who pre-
sent with drug intoxication after either suicidal attempts or accidental overdoses.
3 DRUG-INDUCED NEUROTOXICITY: TRIGGERING AND

SUSCEPTIBILITY FACTORS
The neurotoxicity induced by drugs of abuse is primarily mediated by alterations in
several neurotransmitter systems. However, the severity of these neurotoxic effects
may be significantly affected by a variety of other factors as described below (Fig. 1).
3.1 DRUG-RELATED FACTORS

3.1.1 Active metabolites and adulterants
Neurotoxicity induced by drugs of abuse is influenced by the production of metabolites
that can cross the BBB. For example, the metabolism of cocaine results in the produc-
tion of neurotoxic compounds including benzoylecgonine, norcocaine, and cocaethy-
lene that have their own toxicity profiles (Milhazes et al., 2006; Nassogne et al., 1998).
Metabolism of the amphetamines can produce other active metabolites that are
known to impact neurotransmitter release or reuptake (Smoluch et al., 2014). Heroin
is metabolized to 6-monoacetylmorphine and morphine with potential neurotoxic
consequences (Hu et al., 2002; Mao et al., 2002). Adulterants also play a role in
drug-induced neurotoxicity including the toxicity of heroin that produces more toxicity
in PC12 cells depending on the level of the purity of drugs available to drug addicts
(Oliveira et al., 2002). Highly purified heroin produces less caspase activation than less
pure heroin (Cunha-Oliveira et al., 2007).
3.1.2 Polydrug abuse

The use of multiple drugs by addicts can also impact their clinical presentation and
the adverse consequences of the drugs used by these patients. In addition to their
drugs of choice (primary drug), addicts may use other substance to potentiate or at-
tenuate the behavioral of the primary drug. There are various patterns of polydrug
FIGURE 1
Drug-induced neurotoxicity at a glance: underlying mechanisms and triggering factors. Glu
and DA represent glutamate and dopamine, respectively.
3 Drug-Induced neurotoxicity: Triggering and susceptibility factors 25
abuse (Connor et al., 2014) and the resulting effects of these combinations depend on
the biochemical cascades that are impacted by each one. For example, benzodiaze-
pines are known to influence the pharmacokinetics of opioids ( Jones et al., 2012).
Diazepam acts as both a noncompetitive inhibitor of methadone metabolism
( Jones et al., 2012) and a competitive inhibitor of hepatic N-demethylation of meth-
adone ( Jones et al., 2012). These interactions increase methadone concentration in
brain tissues and may therefore increase the neurotoxic profile of methadone.
Mephedrone, a methamphetamine analog, does not seem to cause neurotoxicity
by itself but increases the neurotoxicity of other drugs of abuse including metham-
phetamine, amphetamine, and MDMA.
3.1.3 Substance withdrawal

Long-term METH withdrawal sensitizes NMDA receptors to agonist exposure
(Smith et al., 2008). Mechanistically, METH withdrawal decreases Mg2+ blockade
of NMDA receptors and results in increased excitatory postsynaptic potentials
(Moriguchi et al., 2002), a phenomenon that may potentiate NMDA-induced neuro-
toxicity. Ethanol withdrawal also leads to neuronal hyperexcitability that manifests
as seizures during various intervals of alcohol withdrawal (Hoffman and Tabakoff,
1994; Lovinger, 1993).
3.2 ENVIRONMENTAL FACTORS

3.2.1 Chronic stress
Chronic stress can alter the neurochemical responses to drugs of abuse. For example,
drug-induced dopamine release increases in several brain regions following preex-
posure to stress (Hamamura and Fibiger, 1993; Kalivas and Duffy, 1989; Rouge-Pont
et al., 1995). Stressful events enhance rats tendency to self-administer drugs of abuse
(Covington and Miczek, 2001; Piazza and Le Moal, 1998), thereby increasing poten-
tial risks of drug-induced neurotoxicity. Chronic stress also increases the hyperther-
mic response to methamphetamine (Tata and Yamamoto, 2008). These data, taken
together, suggest long-term stress can potentiate the vulnerability of brain cells to the
neurotoxic effects of psychostimulants (Matuszewich and Yamamoto, 2004).
3.2.2 Ambient temperature

The neurotoxicity induced by several drugs of abuse including amphetamine, meth-
amphetamine, and 3,4-MDMA are affected by environmental temperature (Bowyer
and Holson, 1995; Bowyer et al., 2001; Miller and O’Callaghan, 1994). Even rela-
tively small variations in ambient temperature can significantly impact neurotoxicity
caused by the amphetamines. Specifically, it has been suggested that increasing the
environmental temperature following D-methamphetamine abuse is equivalent to in-
creasing the dose of the drug (Miller and O’Callaghan, 2003). Similar effects of en-
vironmental temperature have been reported for MDMA. In contrast, lowering
environmental temperature can provide substantial degree of protection ( Johnson
et al., 2000). This phenomenon might play a significant role in clinical emergencies
reported in places where young drug abusers meet to dance and take amphetamine-
like compounds (Chadwick et al., 1991; Randall, 1992).
3.2.3 Diet and nutritional supplies
Nutritional deficiencies may also impact drug toxicity. For example, selenium defi-
ciency potentiates methamphetamine-induced depletion of tyrosine hydroxylase im-
munoreactivity, DA, and its metabolites (Kim et al., 2000). Vitamin E deficiency
also enhances susceptibility to the neurotoxicity induced by D-MDMA in mice
(Johnson et al., 2002). Thiamine deficiency produces mitochondrial dysfunction,
glutamate excitotoxicity, and oxidative stress in different parts of the brain (Todd
and Butterworth, 1999, 2001). This is important because chronic alcoholic patients
commonly suffer from thiamine deficiency (Kopelman et al., 2009; Victor et al.,
1989) due, in part, to the fact that alcohol interferes with the intestinal absorption
of dietary nutrients.
3.3 INDIVIDUAL-RELATED FACTORS

3.3.1 The role of age
Drug-induced neurotoxicity varies in severity according to age (Teuchert-Noodt and
Dawirs, 1991). For example, brain amphetamine levels in old rats are twice as high as
the levels in young ones (Truex and Schmidt, 1980). In fact, older rats experience
greater methamphetamine neurotoxicity than younger animals (Krasnova and
Cadet, 2009). Older mice experience methamphetamine toxicity even after low doses
of the drug, whereas younger rodents show very little or no toxicity even at higher
doses (Miller et al., 2000).
3.3.2 The role of gender

A number of animal studies have reported that methamphetamine induces greater
neurotoxicity in males than females (Miller et al., 1998). MDMA also causes greater
lethality in male mice (Miller and O’Callaghan, 1995). In contrast, women are more
susceptible than men to the possible complications of alcohol abuse (Alfonso-
Loeches et al., 2013).
3.3.3 Gestational drug exposure

Prenatal exposure to methamphetamine increases the risk of neurotoxicity in off-
spring (Heller et al., 2001). The mechanism by which prenatal methamphetamine
exposure could potentiate drug-induced neurotoxicity is not well understood. Be-
cause methamphetamine toxicity is dependent on the functions of DAT and
VMAT-2 (Fumagalli et al., 1999), prenatal exposure to methamphetamine may de-
crease the ability of DAT VMAT-2 to maintain DA homeostasis in DA axon termi-
nals (Heller et al., 2001). Much remains to be done on this subject.
3.3.4 Antioxidant status

Cells contain various biochemical agents that serve to protect them against the toxic
effects of oxygen and it metabolites (Cadet and Brannock, 1998). These antioxidants
include GPx, catalase, and SOD that protect against the toxicity of hydrogen peroxide
4 Drug-Induced neurotoxicity: Potential preventive strategies 27
and superoxide radicals (Cadet and Brannock, 1998). Of relevance to this discussion,
mice deficient in GPx are more susceptible to the adverse effects of neurotoxins
(Zhang et al., 2000). Interestingly, neurons that survive in neurodegenerative diseases
express high concentration of SOD (Browne et al., 1999). The importance of the
balance between toxic prooxidants and innate antioxidant defense mechanisms has
been tested by genetic elimination and augmentation of these pathways. Downregula-
tion of Cu/Zn-SOD increases neuronal death both in vivo and in vitro (Kondo et al.,
1997; Troy et al., 1996). Also, deficiency in a-tocopherol (vitamin E) transport protein
produces neurodegeneration (Yokota et al., 2001). Increasing the expression of SOD
and GPx as well as using SOD mimetics has been reported to be neuroprotective
(Pineda et al., 2001; Pong et al., 2000). Importantly, mice with high levels of
CuZn-SOD are protected against the toxicity of methamphetamine and MDMA
(Cadet et al., 1994a,b).
4 DRUG-INDUCED NEUROTOXICITY: POTENTIAL PREVENTIVE

STRATEGIES
Although mechanisms underlying drug-induced neurotoxic effects are not perfectly
understood, pharmacologic approaches have been proposed for their prevention
Table 1.
Table 1 Potential Pharmacologic Interventions to Prevent Drug-Induced

Neurotoxicity
Antineurotoxic Interventions Pharmacologic Agents Drug Name
Modulating dopamine system Dopamine receptor agonists Pramipexole

Dopamine receptor antagonists Eticlopride
Addressing oxidative challenge Artificial antioxidants N-acetyl-L-cysteine
(NAC)
Natural antioxidants Ascorbic acid
(vitamin C), vitamin E
NMDA receptor blockade NMDA receptor antagonists Memantine,
ketamine
Antiapoptotic approach Agents with antiapoptotic Calpastatin,
property minocycline
Drug rotation approach Opioids Methadone,
morphine,
hydromorphone
Anti-inflammatory approach COX inhibitors Ketoprofen,
indomethacin
Thermoregulatory interventions Barbiturates Phenobarbital
Benzodiazepines Diazepam
4.1 MODULATING BRAIN DOPAMINE LEVELS

As mentioned above, dopamine plays a pivotal role in mediating methamphetamine-
induced neurotoxicity by causing production of dopamine-related reactive oxygen
species (ROS) and oxidative stress. Agents decreasing brain dopamine levels such
as tyrosine hydroxylase inhibitor and a-methyl-p-tyrosine have indeed shown to ex-
ert protective effects against the neurotoxicity induced by methamphetamine in stria-
tal dopaminergic axons (Axt et al., 1990; Gibb and Kogan, 1979; Hotchkiss and
Gibb, 1980; Schmidt and Gibb, 1985; Thomas et al., 2008). Pramipexole, a dopamine
D2/D3 receptor agonist, may cause neuroprotection against methamphetamine-
induced toxicity by reducing dopamine turnover by stimulation of presynaptic dopa-
mine receptors or by increasing antioxidant and trophic properties of the brain (Hall
et al., 1996).
4.2 ADDRESSING OXIDATIVE CHALLENGE

Pretreatment with antioxidants such as N-acetyl-L-cysteine, ascorbic acid, and vita-
min E can protect against psychostimulant-induced neurotoxicity (De Vito and
Wagner, 1989; Fukami et al., 2004; Hashimoto et al., 2004; Wagner et al., 1985).
Increasing mitochondrial energy metabolism through pre- and posttreatment of mice
with L-carnitine that coordinates beta-oxidation in mitochondria C significantly at-
tenuates methamphetamine-induced production of the neurotoxin, 3-nitropropionic
acid in the striatum (Virmani et al., 2002). Formation of peroxynitrite production can
be inhibited by pretreatment with some selective antioxidants (selenium and mela-
tonin), several peroxynitrite decomposition catalysts, and selective neuronal nitric
oxide synthase inhibitors (Imam et al., 2001). Vitamin D has also been shown to exert
protection against methamphetamine toxicity (Cass et al., 2006). This is thought to
be mediated by upregulation of glial cell line-derived neurotrophic factor (Cass et al.,
2006). Vitamin D also enhances glutathione levels and suppresses the production of
inducible nitric oxide synthase (Cass et al., 2006).
4.3 ANTIAPOPTOTIC APPROACH

Preventing the activation of apoptotic processes may also be an effective approach
to protect against drug-induced neurotoxicity. For example, administration of the
dopamine type 1 receptor antagonist (SCH23390) attenuates the activation of Fas-
mediated cell death ( Jayanthi et al., 2005). Melatonin, working as a direct free
radical scavenger, was shown to protect against methamphetamine-induced cell
death (Wisessmith et al., 2009). Melatonin reverses the methamphetamine-induced
decrease in mitochondrial function and phosphorylation of tyrosine hydroxylase
in dopaminergic-cultured cells (Suwanjang et al., 2010). It reduces induction of
Bax, caspase, and cell death in these neurons (Suwanjang et al., 2010). Desipramine
which is a monoamine uptake inhibitor that prevents methamphetamine toxicity
(Wisessmith et al., 2009). Calpastatin, an endogenous protease inhibitor, was also
4 Drug-Induced neurotoxicity: Potential preventive strategies 29
shown to reverse methamphetamine-induced activation of death pathways in dopa-

minergic cell lines (Chetsawang et al., 2012; Suwanjang et al., 2012).
4.4 NMDA RECEPTOR ANTAGONISM

Antagonism of NMDA receptors with ketamine or modulation of glutamate trans-
porter activity in spinal cord was shown to prevent opiate-mediated neurotoxicity
(Bruera and Kim, 2003). Memantine is another NMDA receptor antagonist with
well-known neuroprotective properties (Turski et al., 1991). Memantine is thought
to prevent the cellular damage following activation of NMDA receptors by gluta-
mate. This drug has also been approved in Europe as a therapeutic agent for
moderately severe to severe Alzheimer’s disease (Doraiswamy, 2002). In addition,
antagonism of metabotropic glutamate receptor 5 (mGluR5) has been shown to pre-
vent the degeneration of dopaminergic neurons induced by methamphetamine in rats
(Gołembiowska et al., 2003).
4.5 ROTATION IN DRUGS

Opioid rotation refers to a shift from one opioid to another with the aim of improving
therapeutic effectiveness or reducing adverse effects (Quigley, 2004; Thomsen et al.,
1999). It is a well-accepted clinical method for decreasing drug-induced neurotoxic
effects. Using equipotent therapeutic and nontoxic doses of other opioids can reduce
signs and symptoms of opioid toxicity. Previous studies propose that a variety of two
or three opioids are essential to reach satisfactory long-term effectiveness. Best re-
sults are obtained using morphine, hydromorphone, and methadone in majority of
cases (de Stoutz et al., 1995). For example, in a patient suffering from morphine-
induced neurotoxicity, it was observed that rotation to methadone, which is an opioid
with NMDA antagonistic properties, significantly reduces the morphine neurotoxic
effects (Tarumi et al., 2002). The mechanistic rationale for this approach is that opi-
oid metabolites are involved in the development of opioid-induced neurotoxicity,
and opioid rotation may allow for clearance of toxic metabolites while the analgesic
effect is maintained (de Stoutz et al., 1995).
4.6 ANTI-INFLAMMATORY APPROACH

Neuroinflammatory processes have been reported to be involved in neurotoxicity in-
duced by methamphetamine treatment. Cyclooxygenase (COX) is one of the main
inflammatory mediators that act as the rate-limiting enzyme in prostaglandin biosyn-
thesis. In recent years, there has been an increased interest in use of COX inhibitors
as a therapeutic approach to protect against neurodegeneration (Etminan et al., 2003;
Gasparini et al., 2004; Hoffmann, 2000; Mhatre et al., 2004). In this regard, several
anti-inflammatory agents including ketoprofen and indomethacin protect against
methamphetamine-induced microgliosis and neurotoxicity (Asanuma et al., 2003,
2004). In contrast, a recent study has suggested that COX-2-containing cells appear
to undergo damage during the early stages of methamphetamine-induced neurotox-

icity and that the selective inhibition of this enzyme may actually be detrimental
rather than protective after exposure to toxic doses of methamphetamine (Zhang
et al., 2007). One possible reason for these discrepancies may be related to differ-
ences in methamphetamine metabolism among different animal species since the lat-
ter study was conducted in mice. Thus, it is important to conduct toxicity studies in
rodents that have more similar metabolic pathways to those observed in humans
(Caldwell et al., 1972; Yanagisawa et al., 1997).
4.7 THERMOREGULATORY INTERVENTIONS

Hyperthermia is considered to be an influencing factor in mediating methamphet-
amine neurotoxicity by facilitating ROS production and increasing dopamine oxida-
tion. Increase in body temperature can be attenuated by administration of dopamine
receptor antagonists (Albers and Sonsalla, 1995; Broening et al., 2005; He et al.,
2004). L-Lobeline, a nicotinic receptor ligand, has both temperature-dependent
and -independent neuroprotective effects against methamphetamine neurotoxicity.
These protective effects may be secondary to the fact that lobeline attenuates
methamphetamine-induced changes in dopamine release, hyperthermia, and the
long-term depletion of striatal dopamine and 5-HT content (Eyerman and
Yamamoto, 2005). There is also an evidence indicating that keeping animals in
low environmental temperatures or pretreatment with pharmacologic agents that pro-
duce hypothermia such as MK-801, diazepam, and phenobarbital reduces METH
neurotoxicity (Ali et al., 1994).
5 DRUG-INDUCED NEUROTOXICITY IN ADDICTION MEDICINE

Different populations with substance use disorders could be potential targets for neu-
roprotective interventions.
5.1 TREATMENT SEEKERS

Complete abstinence is not a reasonable and achievable goal for the first few weeks
of treatment (Shoptaw et al., 1994). High levels of compliance for medications and
dietary supplements may facilitate therapeutic plans for neuroprotection against
lapse-induced toxicity.
5.2 NONTREATMENT SEEKERS

There is a long-term interval between initiation of drug use, progression to substance
use disorder, and seeking treatment (Power et al., 1992). This interval could be a crit-
ical period to reduce harm of neurotoxicity by different educational and pharmaco-
logic interventions.
5.3 RELAPSE-PRONE PATIENTS

Patients who receive residential abstinence-based treatment programs for a period of
time are vulnerable to lapses after their discharges from residential centers (Arbour
et al., 2011). A period of abstinence reduces the natural barriers against neurotoxicity
and reexposure to illicit drugs could have serious negative effects.
5.4 INTOXICATED PATIENTS DURING OVERDOSE OR BINGE EPISODES

Large doses of illicit drugs during overdose or binge drug use could activate multiple
pathways of neurotoxicity. Considering pharmacologic and nonpharmacologic (such
as reducing core body temperature) neuroprotective interventions within drug over-
dose management protocols could reduce harm and long-lasting brain sequelae
(Rolland et al., 2011).
5.5 CLIENTS SUFFERING FROM SEVERE DRUG WITHDRAWAL

SYMPTOMS
Approaches to treat potential neurological damage during alcohol withdrawal syn-
drome are often considered during the treatment of these patients (Adinoff, 1994).
However, neuroprotective approaches to other addicted patient populations are often
neglected. This needs to be remedied by development of medications that address
not only drug self-administration but also withdrawal-associated damage to the
brain.

This review has focused on the published literature dealing with the toxic effects of
various licit and illicit drugs. This chapter suggests that the development of agents
that only address self-administration aspects of drug addiction may not be sufficient
to reduce neuropathological complications of these drugs. In reality, the clinical
course of addicted patients is intimately linked to the neurological functioning
of these patients and depends on the abused drugs in question. Therefore, the ad-
dition of neuroprotective agents in conjunction with antiaddictive therapies is war-
ranted in cases such as methamphetamine addiction that is accompanied by the
development of Parkinsonism in some older patients. Nevertheless, because drugs
of abuse appear to exert their neurotoxic effects through distinct molecular path-
ways, understanding the precise biochemical substrates for each agent is of para-
mount importance. Future studies are needed to develop strategies that might
improve the recovery of brain systems affected by repeated exposure to substances
of abuse.
ACKNOWLEDGMENTS
This chapter was supported, in part, by funds of the NIDA Intramural Research Program
(J.L.C.). H.E. has received funds from Tehran University of Medical Sciences for his contri-
bution in this chapter.
REFERENCES
Adinoff, B., 1994. The alcohol withdrawal syndrome. Neurobiology of treatment and toxicity.
Am. J. Addict. 3, 277–288.
Albers, D.S., Sonsalla, P.K., 1995. Methamphetamine-induced hyperthermia and dopaminer-
gic neurotoxicity in mice: pharmacological profile of protective and nonprotective agents.
J. Pharmacol. Exp. Ther. 275 (3), 1104–1114.
Alfonso-Loeches, S., Pascual, M., Guerri, C., 2013. Gender differences in alcohol-induced
neurotoxicity and brain damage. Toxicology 311 (1–2), 27–34.
Ali, S.F., et al., 1994. Low environmental temperatures or pharmacologic agents that produce
hypothermia decrease methamphetamine neurotoxicity in mice. Brain Res. 658 (1–2),
33–38.
Arbour, S., Hambley, J., Ho, V., 2011. Predictors and outcome of aftercare participation of
alcohol and drug users completing residential treatment. Subst. Use Misuse 46 (10),
1275–1287.
Asanuma, M., et al., 2003. Methamphetamine-induced neurotoxicity in mouse brain is atten-
uated by ketoprofen, a non-steroidal anti-inflammatory drug. Neurosci. Lett. 352 (1),
13–16.
Asanuma, M., et al., 2004. Specific gene expression and possible involvement of inflammation
in methamphetamine-induced neurotoxicity. Ann. N. Y. Acad. Sci. 1025, 69–75.
Axt, K.J., et al., 1990. alpha-Methyl-p-tyrosine pretreatment partially prevents
methamphetamine-induced endogenous neurotoxin formation. Brain Res. 515 (1–2),
269–276.
Battaglia, G., Fornai, F., Busceti, C., 2002. Selective blockade of mGlu5 metabotropic gluta-
mate receptors is protective against methamphetamine neurotoxicity. J. Neurosci. 22 (6),
2135–2141. Available at: http://www.jneurosci.org/content/22/6/2135.short. accessed
March 27, 2015.
Bowyer, J.F., Holson, R.R., 1995. Methamphetamine and amphetamine neurotoxicity. In:
Chang, L.W., Dyer, R.S. (Eds.), Handbook of Neurotoxicology. Marcel Dekker, New
York.
Bowyer, J.F., et al., 1994. Further studies of the role of hyperthermia in methamphetamine
neurotoxicity. J. Pharmacol. Exp. Ther. 268 (3), 1571–1580.
Bowyer, J.F., et al., 2001. Phenobarbital and dizocilpine can block methamphetamine-induced
neurotoxicity in mice by mechanisms that are independent of thermoregulation. Brain Res.
919 (1), 179–183.
Broening, H.W., Morford, L.L., Vorhees, C.V., 2005. Interactions of dopamine D1 and D2
receptor antagonists with D-methamphetamine-induced hyperthermia and striatal dopa-
mine and serotonin reductions. Synapse 56 (2), 84–93.
Browne, S.E., Ferrante, R.J., Beal, M.F., 1999. Oxidative stress in Huntington’s disease. Brain
Pathol. (Zurich, Switzerland) 9 (1), 147–163.
References 33
Bruera, E., Kim, H.N., 2003. Cancer pain. JAMA 290 (18), 2476–2479.
Cadet, J.L., Bisagno, V., 2014. Glial-neuronal ensembles: partners in drug addiction-
associated synaptic plasticity. Front. Pharmacol. 5, 204.
Cadet, J.L., Brannock, C., 1998. Free radicals and the pathobiology of brain dopamine sys-
tems. Neurochem. Int. 32 (2), 117–131.
Cadet, J.L., Sheng, P., et al., 1994a. Attenuation of methamphetamine-induced neurotox-
icity in copper/zinc superoxide dismutase transgenic mice. J. Neurochem. 62 (1),
380–383.
Cadet, J.L., Ali, S., Epstein, C., 1994b. Involvement of oxygen-based radicals in
methamphetamine-induced neurotoxicity: evidence from the use of CuZnSOD transgenic
mice. Ann. N. Y. Acad. Sci. 738, 388–391.
Cadet, J.L., Krasnova, I.N., Jayanthi, S., Lyles, J., 2007. Neurotoxicity of substituted amphet-
amines: molecular and cellular mechanisms. Neurotox. Res. 11 (3–4), 183–202.
Cadet, J.L., Bisagno, V., Milroy, C.M., 2014. Neuropathology of substance use disorders. Acta
Neuropathol. 127 (1), 91–107.
Caldwell, J., Dring, L.G., Williams, R.T., 1972. Metabolism of (14 C)methamphetamine in
man, the guinea pig and the rat. Biochem. J. 129 (1), 11–22.
Capela, J.P., Ruscher, K., Lautenschlager, M., Freyer, D., Dirnagl, U., Gaio, A.R., Bastos, M.L.,
Meisel, A., Carvalho, F., 2006. Ecstasy-induced cell death in cortical neuronal cultures is
serotonin 2A-receptor-dependent and potentiated under hyperthermia. Neuroscience
139 (3), 1069–1081.
Capela, J.P., et al., 2009. Molecular and cellular mechanisms of ecstasy-induced neurotoxic-
ity: an overview. Mol. Neurobiol. 39 (3), 210–271.
Cass, W.A., Smith, M.P., Peters, L.E., 2006. Calcitriol protects against the dopamine- and
serotonin-depleting effects of neurotoxic doses of methamphetamine. Ann. N. Y. Acad.
Sci. 1074, 261–271.
Chadwick, I.S., et al., 1991. Ecstasy, 3-4 methylenedioxymethamphetamine (MDMA), a fa-
tality associated with coagulopathy and hyperthermia. J. R. Soc. Med. 84 (6), 371.
Chetsawang, J., et al., 2012. Calpastatin reduces methamphetamine-induced induction in c-Jun
phosphorylation, Bax and cell death in neuroblastoma SH-SY5Y cells. Neurosci. Lett.
506 (1), 7–11.
Chipana, C., Torres, I., Camarasa, J., Pubill, D., Escubedo, E., 2008. Memantine protects against
amphetamine derivatives-induced neurotoxic damage in rodents. Neuropharmacology
54 (8), 1254–1263.
Connor, J.P., et al., 2014. Polysubstance use: diagnostic challenges, patterns of use and health.
Curr. Opin. Psychiatry 27 (4), 269–275.
Covington 3rd., H.E., Miczek, K.A., 2001. Repeated social-defeat stress, cocaine or morphine.
Effects on behavioral sensitization and intravenous cocaine self-administration “binges”.
Psychopharmacology 158 (4), 388–398.
Cunha-Oliveira, T., Rego, A.C., Cardoso, S.M., Borges, F., Swerdlow, R.H., Macedo, T., de
Oliveira, C.R., 2006. Mitochondrial dysfunction and caspase activation in rat cortical neu-
rons treated with cocaine or amphetamine. Brain Res. 1089 (1), 44–54.
Cunha-Oliveira, T., et al., 2007. Street heroin induces mitochondrial dysfunction and apopto-
sis in rat cortical neurons. J. Neurochem. 101 (2), 543–554. Available at: http://www.ncbi.
nlm.nih.gov/pubmed/17250679.
Cunha-Oliveira, T., et al., 2010. Neurotoxicity of heroin-cocaine combinations in rat cortical
neurons. Toxicology 276 (1), 11–17. Available at: http://www.ncbi.nlm.nih.gov/pubmed/
20600547. accessed March 27, 2015.
Cunningham, K.A., Paris, J.M., Goeders, N.E., 1992. Chronic cocaine enhances serotonin
autoregulation and serotonin uptake binding. Synapse 11 (2), 112–123.
De Stoutz, N.D., Bruera, E., Suarez-Almazor, M., 1995. Opioid rotation for toxicity reduction
in terminal cancer patients. J. Pain Symptom Manag. 10 (5), 378–384.
De Vito, M.J., Wagner, G.C., 1989. Methamphetamine-induced neuronal damage: a possible
role for free radicals. Neuropharmacology 28 (10), 1145–1150.
Dey, S., et al., 2007. Cocaine exposure in vitro induces apoptosis in fetal locus coeruleus neu-
rons by altering the Bax/Bcl-2 ratio and through caspase-3 apoptotic signaling.
Neuroscience 144 (2), 509–521. Available at: http://www.pubmedcentral.nih.gov/
articlerender.fcgi?artid¼2562674&tool¼pmcentrez&rendertype¼abstract.
Dietrich, J.-B., et al., 2005. Acute or repeated cocaine administration generates reactive ox-
ygen species and induces antioxidant enzyme activity in dopaminergic rat brain structures.
Neuropharmacology 48 (7), 965–974. Available at: http://www.ncbi.nlm.nih.gov/
pubmed/15857623.
Dolin, S., et al., 1987. Increased dihydropyridine-sensitive calcium channels in rat brain may
underlie ethanol physical dependence. Neuropharmacology 26 (2–3), 275–279.
Domercq, M., Matute, C., 2004. Neuroprotection by tetracyclines. Trends Pharmacol. Sci.
25 (12), 609–612. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15530637.
Doraiswamy, P.M., 2002. Non-cholinergic strategies for treating and preventing Alzheimer’s
disease. CNS Drugs 16 (12), 811–824.
Escubedo, E., et al., 1998. Microgliosis and down-regulation of adenosine transporter induced
by methamphetamine in rats. Brain Res. 814 (1–2), 120–126.
Etminan, M., Gill, S., Samii, A., 2003. Effect of non-steroidal anti-inflammatory drugs on risk
of Alzheimer’s disease: systematic review and meta-analysis of observational studies.
BMJ 327 (7407), 128.
Eyerman, D.J., Yamamoto, B.K., 2005. Lobeline attenuates methamphetamine-induced
changes in vesicular monoamine transporter 2 immunoreactivity and monoamine deple-
tions in the striatum. J. Pharmacol. Exp. Ther. 312 (1), 160–169.
Fukami, G., et al., 2004. Effect of antioxidant N-acetyl-L-cysteine on behavioral changes and
neurotoxicity in rats after administration of methamphetamine. Brain Res. 1016 (1),
90–95.
Fuller, R.W., Hemrick-Luecke, S.K., Ornstein, P.L., 1992. Protection against amphetamine-
induced neurotoxicity toward striatal dopamine neurons in rodents by LY274614, an ex-
citatory amino acid antagonist. Neuropharmacology 31 (10), 1027–1032.
Fumagalli, F., et al., 1999. Increased methamphetamine neurotoxicity in heterozygous vesic-
ular monoamine transporter 2 knock-out mice. J. Neurosci. Off. J. Soc. Neurosci. 19 (7),
2424–2431.
Gasparini, L., et al., 2004. Modulation of beta-amyloid metabolism by non-steroidal anti-
inflammatory drugs in neuronal cell cultures. J. Neurochem. 88 (2), 337–348.
Gibb, J.W., Kogan, F.J., 1979. Influence of dopamine synthesis on methamphetamine-induced
changes in striatal and adrenal tyrosine hydroxylase activity. Naunyn Schmiedeberg’s
Arch. Pharmacol. 310 (2), 185–187. Available at: http://link.springer.com/10.1007/
BF00500283.
Gołembiowska, K., et al., 2003. Neuroprotective action of MPEP, a selective mGluR5 antag-
onist, in methamphetamine-induced dopaminergic neurotoxicity is associated with a de-
crease in dopamine outflow and inhibition of hyperthermia in rats. Neuropharmacology
References 35
45 (4), 484–492. Available at: http://www.sciencedirect.com/science/article/pii/

S0028390803002090. accessed March 27, 2015.
Graham, D.G., Tiffany, S.M., Bell Jr., W.R., Gutknecht, W.F., 1978. Autoxidation versus co-
valent binding of quinones as the mechanism of toxicity of dopamine,
6-hydroxydopamine, and related compounds toward C1300. Mol. Pharmacol. 14 (4),
644–653. Available at: http://molpharm.aspetjournals.org/content/14/4/644.short.
accessed March 27, 2015.
Guilarte, T.R., et al., 2003. Methamphetamine-induced deficits of brain monoaminergic neu-
ronal markers: distal axotomy or neuronal plasticity. Neuroscience 122 (2), 499–513.
Hall, E.D., et al., 1996. Neuroprotective effects of the dopamine D2/D3 agonist pramipexole
against postischemic or methamphetamine-induced degeneration of nigrostriatal neurons.
Brain Res. 742 (1–2), 80–88.
Hamamura, T., Fibiger, H.C., 1993. Enhanced stress-induced dopamine release in the prefron-
tal cortex of amphetamine-sensitized rats. Eur. J. Pharmacol. 237 (1), 65–71.
Hashimoto, K., et al., 2004. Protective effects of N-acetyl-L-cysteine on the reduction of do-
pamine transporters in the striatum of monkeys treated with methamphetamine.
Neuropsychopharmacology 29 (11), 2018–2023.
Hawkins, B.T., Davis, T.P., 2005. The blood–brain barrier/neurovascular unit in health and
disease. Pharmacol. Rev. 57 (2), 173–185.
Hawkins, B.T., et al., 2004. Nicotine increases in vivo blood–brain barrier permeability and al-
ters cerebral microvascular tight junction protein distribution. Brain Res. 1027 (1–2), 48–58.
He, J., et al., 2004. Neuroprotective effects of olanzapine on methamphetamine-induced neu-
rotoxicity are associated with an inhibition of hyperthermia and prevention of Bcl-2 de-
crease in rats. Brain Res. 1018 (2), 186–192.
Heller, A., et al., 2001. Gender-dependent enhanced adult neurotoxic response to methamphet-
amine following fetal exposure to the drug. J. Pharmacol. Exp. Ther. 298 (2), 769–779.
Hoffman, P.L., Tabakoff, B., 1994. The role of the NMDA receptor in ethanol withdrawal.
EXS 71, 61–70.
Hoffmann, C., 2000. COX-2 in brain and spinal cord implications for therapeutic use. Curr.
Med. Chem. 7 (11), 1113–1120.
Hotchkiss, A.J., Gibb, J.W., 1980. Long-term effects of multiple doses of methamphetamine
on tryptophan hydroxylase and tyrosine hydroxylase activity in rat brain. J. Pharmacol.
Exp. Ther. 214 (2), 257–262.
Hu, S., et al., 2002. Morphine induces apoptosis of human microglia and neurons.
Neuropharmacology 42 (6), 829–836. Available at: http://linkinghub.elsevier.com/re
trieve/pii/S0028390802000308.
Imam, S.Z., et al., 2001. Methamphetamine-induced dopaminergic neurotoxicity: role of per-
oxynitrite and neuroprotective role of antioxidants and peroxynitrite decomposition cata-
lysts. Ann. N. Y. Acad. Sci. 939, 366–380.
Imam, S.Z., Duhart, H.M., Skinner, J.T., Ali, S.F., 2005. Cocaine induces a differential dose-
dependent alteration in the expression profile of immediate early genes, transcription fact
ors, and caspases in PC12 cells: a possible mechanism of neurotoxic damage in cocaine
addiction. Ann. N. Y. Acad. Sci. 1053, 482–490.
Jayanthi, S., et al., 2004. Methamphetamine induces neuronal apoptosis via cross-talks be-
tween endoplasmic reticulum and mitochondria-dependent death cascades. FASEB J.
18 (2), 238–251.
Jayanthi, S., et al., 2005. Calcineurin/NFAT-induced up-regulation of the Fas ligand/Fas death
pathway is involved in methamphetamine-induced neuronal apoptosis. Proc. Natl. Acad.
Sci. USA 102 (3), 868–873.
Jayanthi, S., et al., 2009. Methamphetamine induces dopamine D1 receptor-dependent endo-
plasmic reticulum stress-related molecular events in the rat striatum. PLoS One 4 (6),
e6092.
Johnson, E.A., Sharp, D.S., Miller, D.B., 2000. Restraint as a stressor in mice: against the do-
paminergic neurotoxicity of D-MDMA, low body weight mitigates restraint-induced hy-
pothermia and consequent neuroprotection. Brain Res. 875 (1–2), 107–118.
Johnson, E.A., et al., 2002. d-MDMA during vitamin E deficiency: effects on dopaminergic
neurotoxicity and hepatotoxicity. Brain Res. 933 (2), 150–163.
Jones, J.D., Mogali, S., Comer, S.D., 2012. Polydrug abuse: a review of opioid and benzodi-
azepine combination use. Drug Alcohol Depend. 125 (1–2), 8–18.
Kalant, H., Kalant, O.J., 1975. Death in amphetamine users: causes and rates. Can. Med.
Assoc. J. 112 (3), 299–304.
Kalivas, P.W., Duffy, P., 1989. Similar effects of daily cocaine and stress on mesocorticolim-
bic dopamine neurotransmission in the rat. Biol. Psychiatry 25 (7), 913–928.
Kim, H., et al., 2000. Selenium deficiency potentiates methamphetamine-induced nigral neu-
ronal loss; comparison with MPTP model. Brain Res. 862 (1–2), 247–252.
Kondo, T., et al., 1997. Reduction of CuZn-superoxide dismutase activity exacerbates neuro-
nal cell injury and edema formation after transient focal cerebral ischemia. J. Neurosci.
Off. J. Soc. Neurosci. 17 (11), 4180–4189.
Kopelman, M.D., et al., 2009. The Korsakoff syndrome: clinical aspects, psychology and treat-
ment. Alcohol Alcohol. 44 (2), 148–154.
Koppi, S., et al., 1987. Calcium-channel-blocking agent in the treatment of acute alcohol
withdrawal—caroverine versus meprobamate in a randomized double-blind study.
Neuropsychobiology 17 (1–2), 49–52.
Kousik, S.M., et al., 2011. Methamphetamine-induced vascular changes lead to striatal hyp-
oxia and dopamine reduction. Neuroreport 22 (17), 923–928.
Krasnova, I.N., Cadet, J.L., 2009. Methamphetamine toxicity and messengers of death. Brain
Res. Rev. 60 (2), 379–407.
Krasnova, I.N., Ladenheim, B., Cadet, J.L., 2005. Amphetamine induces apoptosis of medium
spiny striatal project ion neurons via the mitochondria-dependent pathway. FASEB J.
19 (7), 851–853.
Kroemer, G., Martin, S.J., 2005. Caspase-independent cell death. Nat. Med. 11 (7), 725–730.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/16015365.
Langlais, P., Mair, R., 1990. Protective effects of the glutamate antagonist MK-801 on
pyrithiamine-induced lesions and amino acid changes in rat brain. J. Neurosci. 10 (5),
1664–1674. Available at: http://www.jneurosci.org/content/10/5/1664.short. accessed
March 27, 2015.
Levy, A.D., Baumann, M.H., Van de Kar, L.D., 1994. Monoaminergic regulation of neuro-
endocrine function and its modification by cocaine. Front. Neuroendocrinol. 15 (2),
85–156.
Lin, P.S., et al., 1991. Hyperthermia enhances the cytotoxic effects of reactive oxygen species
to Chinese hamster cells and bovine endothelial cells in vitro. Radiat. Res. 126 (1), 43–51.
Lin, S.J., et al., 1992. Long-term nicotine exposure increases aortic endothelial cell death and
enhances transendothelial macromolecular transport in rats. Arterioscler. Thromb. 12 (11),
1305–1312.
References 37
Lipton, J.W., et al., 2003. Prenatal cocaine administration increases glutathione and alpha-
tocopherol oxidation in fetal rat brain. Dev. Brain Res. 147 (1–2), 77–84. Available at:
http://linkinghub.elsevier.com/retrieve/pii/S0165380603002475. accessed March 27, 2015.
Little, H.J., Dolin, S.J., Halsey, M.J., 1986. Calcium channel antagonists decrease the ethanol
withdrawal syndrome. Life Sci. 39 (22), 2059–2065.
Lovinger, D.M., 1993. Excitotoxicity and alcohol-related brain damage. Alcohol. Clin. Exp.
Res. 17 (1), 19–27.
Lyles, J., Cadet, J.L., 2003. Methylenedioxymethamphetamine (MDMA, Ecstasy) neurotox-
icity: cellular and molecular mechanisms. Brain Res. Brain Res. Rev. 42 (2), 155–168.
Macêdo, D.S., et al., 2005. Cocaine alters catalase activity in prefrontal cortex and striatum of
mice. Neurosci. Lett. 387 (1), 53–56. Available at: http://www.ncbi.nlm.nih.gov/pubmed/
16085363.
Mao, J., et al., 2002. Neuronal apoptosis associated with morphine tolerance: evidence for an
opioid-induced neurotoxic mechanism. J. Neurosci. 22 (17), 7650–7661. Available at:
http://www.jneurosci.org/content/22/17/7650.short. accessed March 27, 2015.
Martin, D., Cohen, S., Morrisett, R.A., 1991. Ethanol effects upon rat hippocampal epilepti-
form activity. Alcohol. Clin. Exp. Res. 15, 324.
Matuszewich, L., Yamamoto, B.K., 2004. Chronic stress augments the long-term and acute
effects of methamphetamine. Neuroscience 124 (3), 637–646.
Mhatre, M., Floyd, R.A., Hensley, K., 2004. Oxidative stress and neuroinflammation in Alz-
heimer’s disease and amyotrophic lateral sclerosis: common links and potential therapeu-
tic targets. J. Alzheimer’s Dis. 6 (2), 147–157.
Milhazes, N., et al., 2006. Synthesis and cytotoxic profile of 3,4-
methylenedioxymethamphetamine (“ecstasy”) and its metabolites on undifferentiated
PC12 cells: a putative structure-toxicity relationship. Chem. Res. Toxicol. 19 (10),
1294–1304.
Miller, D.B., O’Callaghan, J.P., 1994. Environment-, drug- and stress-induced alterations in
body temperature affect the neurotoxicity of substituted amphetamines in the C57BL/6J
mouse. J. Pharmacol. Exp. Ther. 270 (2), 752–760.
Miller, D.B., O’Callaghan, J.P., 1995. The role of temperature, stress, and other factors in the
neurotoxicity of the substituted amphetamines 3,4-methylenedioxymethamphetamine and
fenfluramine. Mol. Neurobiol. 11 (1–3), 177–192.
Miller, D.B., O’Callaghan, J.P., 2003. Elevated environmental temperature and methamphet-
amine neurotoxicity. Environ. Res. 92 (1), 48–53.
Miller, D.B., et al., 1998. The impact of gender and estrogen on striatal dopaminergic neuro-
toxicity. Ann. N. Y. Acad. Sci. 844, 153–165.
Miller, D.B., O’Callaghan, J.P., Ali, S.F., 2000. Age as a susceptibility factor in the striatal
dopaminergic neurotoxicity observed in the mouse following substituted amphetamine ex-
posure. Ann. N. Y. Acad. Sci. 914, 194–207.
Mitchell, E.S., Snyder-Keller, A., 2003. c-fos and cleaved caspase-3 expression after perinatal
exposure to ethanol, cocaine, or the combination of both drugs. Dev. Brain Res. 147 (1–2),
107–117. Available at: http://linkinghub.elsevier.com/retrieve/pii/S0165380603002700.
Monks, T.J., et al., 2004. The role of metabolism in 3,4-(+)-methylenedioxyamphetamine and
3,4-(+)-methylenedioxymethamphetamine (ecstasy) toxicity. Ther. Drug Monit. 26 (2),
132–136.
Moriguchi, S., et al., 2002. Enhancement of N-methyl-D-aspartate receptor-mediated excit-
atory postsynaptic potentials in the neostriatum after methamphetamine sensitization.
An in vitro slice study. Exp. Brain Res. 144 (2), 238–246.
Nassogne, M.C., Evrard, P., Courtoy, P.J., 1998. Selective direct toxicity of cocaine on fetal
mouse neurons. Teratogenic implications of neurite and apoptotic neuronal loss. Ann. N.
Y. Acad. Sci. 846, 51–68.
Ohmori, T., Koyama, T., Muraki, A., Yamashita, I., 1993. Competitive and noncompetitive
N-methyl-D-aspartate antagonists protect dopaminergic and serotonergic neurotoxicity
produced by methamphetamine in various brain regions. J. Neural Transm. Gen. Sect.
92 (2–3), 970106.
Oliveira, M.T., et al., 2002. Toxic effects of opioid and stimulant drugs on undifferentiated
PC12 cells. Ann. N. Y. Acad. Sci. 965, 487–496. Available at: http://doi.wiley.com/
10.1111/j.1749-6632.2002.tb04190.x.
Oliveira, M.T., et al., 2003. Drugs of abuse induce apoptotic features in PC12 cells. Ann. N. Y.
Acad. Sci. 1010 (1), 667–670. Available at: http://doi.wiley.com/10.1196/annals.1299.121.
Oliveira, M.F., Norremose, K.A., Oliveira, O.P., Guimarães, W.V., Sekeff, F.A., 2011. Cartas
aos editores. Glutamatergic excitotoxicity secondary to status epilepticus after crack
abuse: a case report Excitotoxicidade glutamatérgica secundária ao uso de crack: relato
de caso. Rev. Bras. Psiquiatr. 33 (2), 209–210.
Omar, R.A., Yano, S., Kikkawa, Y., 1987. Antioxidant enzymes and survival of normal and
simian virus 40-transformed mouse embryo cells after hyperthermia. Cancer Res. 47 (13),
3473–3476.
Ozmen, I., Naziroğlu, M., Alici, H.A., Sahin, F., Cengiz, M., Eren, I., 2007. Spinal morphine
administration reduces the fatty acid contents in spinal cord and brain by increasing ox-
idative stress. Neurochem. Res. 32 (1), 19–25.
Piazza, P.V., Le Moal, M., 1998. The role of stress in drug self-administration. Trends Phar-
macol. Sci. 19 (2), 67–74.
Pineda, J.A., et al., 2001. Extracellular superoxide dismutase overexpression improves behav-
ioral outcome from closed head injury in the mouse. J. Neurotrauma 18 (6), 625–634.
Pong, K., Doctrow, S.R., Baudry, M., 2000. Prevention of 1-methyl-4-phenylpyridinium- and
6-hydroxydopamine-induced nitration of tyrosine hydroxylase and neurotoxicity by EUK-
134, a superoxide dismutase and catalase mimetic, in cultured dopaminergic neurons.
Brain Res. 881 (2), 182–189.
Poon, H.F., et al., 2007. Cocaine-induced oxidative stress precedes cell death in human neu-
ronal progenitor cells. Neurochem. Int. 50 (1), 69–73. Available at: http://linkinghub.
elsevier.com/retrieve/pii/S0197018606002403.
Power, R., Hartnoll, R., Chalmers, C., 1992. Help-seeking among illicit drug users: some dif-
ferences between a treatment and nontreatment sample. Int. J. Addict. 27 (8), 887–904.
Qiusheng, Z., Yuntao, Z., Rongliang, Z., Dean, G., Changling, L., 2005. Effects of verbasco-
side and luteolin on oxidative damage in brain of heroin treated mice. Pharmazie 60 (7),
539–543.
Quigley, C., 2004. Opioid switching to improve pain relief and drug tolerability. Cochrane
Database Syst. Rev. 2004 (3), CD004847.
Randall, T., 1992. Ecstasy-fueled “rave” parties become dances of death for English youths.
JAMA 268 (12), 1505–1506.
Rego, A., Oliveira, C., 2003. Mitochondrial dysfunction and reactive oxygen species in exci-
totoxicity and apoptosis: implications for the pathogenesis of neurodegenerative diseases.
Neurochem. Res. 28 (10), 1563–1574. Available at: http://link.springer.com/article/10.
1023/A:1025682611389. accessed March 27, 2015.
References 39
Reid, M., Hsu, K., Berger, S., 1997. Cocaine and amphetamine preferentially stimulate gluta-
mate release in the limbic system: studies on the involvement of dopamine. Synapse
27 (2), 95–105. Available at: http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1098-2396
(199710)27:2%3C95::AID-SYN1%3E3.0.CO;2-6/abstract. accessed March 27, 2015.
Rolland, B., et al., 2011. Pharmaceutical approaches of binge drinking. Curr. Pharm. Des.
17 (14), 1333–1342.
Rouge-Pont, F., et al., 1995. Stress-induced sensitization and glucocorticoids. II. Sensitization
of the increase in extracellular dopamine induced by cocaine depends on stress-induced
corticosterone secretion. J. Neurosci. Off. J. Soc. Neurosci. 15 (11), 7189–7195.
Sandoval, V., Hanson, G.R., Fleckenstein, A.E., 2000. Methamphetamine decreases mouse
striatal dopamine transporter activity: roles of hyperthermia and dopamine. Eur. J. Phar-
macol. 409 (3), 265–271.
Schmidt, C.J., Gibb, J.W., 1985. Role of the dopamine uptake carrier in the neurochemical
response to methamphetamine: effects of amfonelic acid. Eur. J. Pharmacol. 109 (1),
73–80.
Sekine, Y., et al., 2008. Methamphetamine causes microglial activation in the brains of human
abusers. J. Neurosci. Off. J. Soc. Neurosci. 28 (22), 5756–5761.
Sharma, H.S., 2007. Methods to produce hyperthermia-induced brain dysfunction. Prog. Brain
Res. 162, 173–199.
Sharma, H.S., Ali, S.F., 2008. Acute administration of 3,4-methylenedioxymethamphetamine
induces profound hyperthermia, blood–brain barrier disruption, brain edema formation,
and cell injury. Ann. N. Y. Acad. Sci. 1139, 242–258.
Sharma, H.S., Olsson, Y., Dey, P.K., 1990. Changes in blood–brain barrier and cerebral blood
flow following elevation of circulating serotonin level in anesthetized rats. Brain Res.
517 (1–2), 215–223.
Shoptaw, S., et al., 1994. The Matrix model of outpatient stimulant abuse treatment: evidence
of efficacy. J. Addict. Dis. 13 (4), 129–141.
Skattebol, A., Rabin, R.A., 1987. Effects of ethanol on 45Ca2 + uptake in synaptosomes and in
PC12 cells. Biochem. Pharmacol. 36 (13), 2227–2229.
Smith, K.J., et al., 2008. Potentiation of N-methyl-D-aspartate receptor-mediated neuronal in-
jury during methamphetamine withdrawal in vitro requires co-activation of IP3 receptors.
Brain Res. 1187, 67–73.
Smoluch, M., et al., 2014. Determination of psychostimulants and their metabolites by elec-
trochemistry linked on-line to flowing atmospheric pressure afterglow mass spectrometry.
Analyst 139 (17), 4350–4355.
Sonsalla, P., Nicklas, W., Heikkila, R., 1989. Role for excitatory amino acids in
methamphetamine-induced nigrostriatal dopaminergic toxicity. Science 243 (4889),
398–400. Available at: http://www.sciencemag.org/cgi/doi/10.1126/science.2563176.
Suwanjang, W., et al., 2010. The protective effect of melatonin on methamphetamine-induced
calpain-dependent death pathway in human neuroblastoma SH-SY5Y cultured cells.
J. Pineal Res. 48 (2), 94–101.
Suwanjang, W., et al., 2012. Calpastatin reduces calpain and caspase activation in
methamphetamine-induced toxicity in human neuroblastoma SH-SY5Y cultured cells.
Neurosci. Lett. 526 (1), 49–53.
Tarumi, Y., Pereira, J., Watanabe, S., 2002. Methadone and fluconazole: respiratory depres-
sion by drug interaction. J. Pain Symptom Manag. 23 (2), 148–153.
Tata, D.A., Yamamoto, B.K., 2008. Chronic stress enhances methamphetamine-induced ex-
tracellular glutamate and excitotoxicity in the rat striatum. Synapse 62 (5), 325–336.
Teuchert-Noodt, G., Dawirs, R.R., 1991. Age-related toxicity in prefrontal cortex and caudate-
putamen complex of gerbils (Meriones unguiculatus) after a single dose of methamphet-
amine. Neuropharmacology 30 (7), 733–743.
Thomas, D.M., Kuhn, D.M., 2005. Attenuated microglial activation mediates tolerance to the
neurotoxic effects of methamphetamine. J. Neurochem. 92 (4), 790–797.
Thomas, D.M., Francescutti-Verbeem, D.M., et al., 2004a. Identification of differentially reg-
ulated transcripts in mouse striatum following methamphetamine treatment—an oligonu-
cleotide microarray approach. J. Neurochem. 88 (2), 380–393.
Thomas, D.M., Walker, P.D., et al., 2004b. Methamphetamine neurotoxicity in dopamine
nerve endings of the striatum is associated with microglial activation. J. Pharmacol.
Exp. Ther. 311 (1), 1–7.
Thomas, D.M., Francescutti-Verbeem, D.M., Kuhn, D.M., 2008. The newly synthesized pool
of dopamine determines the severity of methamphetamine-induced neurotoxicity.
J. Neurochem. 105 (3), 605–616.
Thomsen, A.B., Becker, N., Eriksen, J., 1999. Opioid rotation in chronic non-malignant pain
patients. A retrospective study. Acta Anaesthesiol. Scand. 43 (9), 918–923.
Todd, K., Butterworth, R.F., 1999. Mechanisms of selective neuronal cell death due to thia-
mine deficiency. Ann. N. Y. Acad. Sci. 893, 404–411.
Todd, K.G., Butterworth, R.F., 2001. In vivo microdialysis in an animal model of neurological
disease: thiamine deficiency (Wernicke) encephalopathy. Methods (San Diego, Calif.)
23 (1), 55–61.
Tramullas, M., Martı́nez-Cué, C., Hurlé, M.A., 2008. Chronic administration of heroin to mice
produces up-regulation of brain apoptosis-related proteins and impairs spatial learning and
memory. Neuropharmacology 54 (4), 640–652. Available at: http://www.ncbi.nlm.nih.
gov/pubmed/18201731. accessed March 27, 2015.
Troy, C.M., et al., 1996. Downregulation of Cu/Zn superoxide dismutase leads to cell death via
the nitric oxide-peroxynitrite pathway. J. Neurosci. Off. J. Soc. Neurosci. 16 (1), 253–261.
Truex, L.L., Schmidt, M.J., 1980. 3H-amphetamine concentrations in the brains of young and
aged rats: implications for assessment of drug effects in aged animals. Neurobiol. Aging
1 (1), 93–95.
Turski, L., et al., 1991. Protection of substantia nigra from MPP + neurotoxicity by N-methyl-
D-aspartate antagonists. Nature 349 (6308), 414–418.
Uys, J.D., Reissner, K.J., 2011. Glutamatergic neuroplasticity in cocaine addiction. Prog. Mol.
Biol. Transl. Sci. 98, 367–400. Available at: http://www.ncbi.nlm.nih.gov/pubmed/
21199777.
Victor, M., Adams, R.D., Collins, H., 1989. Wernicke-Korsakof Syndrome and Related Neu-
rologic Disorders due to Alcoholism and Malnutrition. FA Davies Company, Philadelphia,
PA, USA.
Virmani, A., et al., 2002. The protective role of L-carnitine against neurotoxicity evoked by
drug of abuse, methamphetamine, could be related to mitochondrial dysfunction. Ann. N.
Y. Acad. Sci. 965, 225–232.
Wagner, G.C., Carelli, R.M., Jarvis, M.F., 1985. Pretreatment with ascorbic acid attenuates the
neurotoxic effects of methamphetamine in rats. Res. Commun. Chem. Pathol. Pharmacol.
47 (2), 221–228.
References 41
Waren, M.W., et al., 2007. Calpain and caspase proteolytic markers co-localize with rat cor-
tical neurons after exposure to methamphetamine and MDMA. Acta Neuropathol. 114 (3),
277086.
Weihmuller, F.B., O’Dell, S.J., Marshall, J.F., 1992. MK-801 protection against
methamphetamine-induced striatal dopamine terminal injury is associated with attenuated
dopamine overflow. Synapse 11 (2), 155–163.
Williams, J.M., Steketee, J.D., 2004. Cocaine increases medial prefrontal cortical glutamate
overflow in cocaine-sensitized rats: a time course study. Eur. J. Neurosci. 20 (6),
1639–1646. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15355331.
Wisessmith, W., et al., 2009. Melatonin reduces induction of Bax, caspase and cell death in
methamphetamine-treated human neuroblastoma SH-SY5Y cultured cells. J. Pineal Res.
46 (4), 433–440.
Wolf, M.E., et al., 2000. Amphetamine increases glutamate efflux in the rat ventral tegmental
area by a mechanism involving glutamate transporters and reactive oxygen species.
J. Neurochem. 75 (4), 1634–1644. Available at: http://doi.wiley.com/10.1046/j.1471-
4159.2000.0751634.x.
Xu, B., Wang, Z., Li, G., Li, B., Lin, H., Zheng, R., Zheng, Q., 2006. Heroin-administered mice
involved in oxidative stress and exogenous antioxidant-alleviated withdrawal syndrome.
Basic Clin. Pharmacol. Toxicol. 99 (2), 153–161.
Yamamoto, B.K., Bankson, M.G., 2005. Amphetamine neurotoxicity: cause and consequence of
oxidative stress. Crit. Rev. Neurobiol. 17 (2), 87–117. Available at: http://www.dl.
begellhouse.com/journals/7b004699754c9fe6,04c698ea6529efba,51741a1b2a4b5a60.html.
Yanagisawa, Y., Nakazato, K., Nagai, T., 1997. Binding of methamphetamine to serum albu-
min in various species in vitro. Pharmacol. Res. 35 (2), 99–102.
Yokota, T., et al., 2001. Delayed-onset ataxia in mice lacking alpha-tocopherol transfer pro-
tein: model for neuronal degeneration caused by chronic oxidative stress. Proc. Natl. Acad.
Sci. USA 98 (26), 15185–15190.
Zhang, J., et al., 2000. Enhanced N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice
deficient in CuZn-superoxide dismutase or glutathione peroxidase. J. Neuropathol. Exp.
Neurol. 59 (1), 53–61.
Zhang, X., et al., 2007. Selective inhibition of cyclooxygenase-2 exacerbates
methamphetamine-induced dopamine depletion in the striatum in rats. Neuroscience
150 (4), 950–958.
CHAPTER
Stress psychobiology in
the context of addiction
medicine: from drugs
of abuse to behavioral
3
addictions
Andrine Lemieux, Mustafa al’Absi1
1
Corresponding author: Tel.: +1-218-726-7122; Fax: +1-218-726-7559
Abstract
In this chapter, we briefly review the basic biology of psychological stress and the stress re-
sponse. We propose that psychological stress and the neurobiology of the stress response play
in substance use initiation, maintenance, and relapse. The proposed mechanisms for this in-
clude, on the one hand, the complex interactions between biological mediators of the stress
response and the dopaminergic reward system and, on the other hand, mediators of the stress
response and other systems crucial in moderating key addiction-related behaviors such as en-
dogenous opioids, the sympathetic-adrenal-medullary system, and endocannabinoids. Excit-
ing new avenues of study including genomics, sex as a moderator of the stress response,
and behavioral addictions (gambling, hypersexuality, dysfunctional internet use, and food
as an addictive substance) are also briefly presented within the context of stress as a moderator
of the addictive process.
Keywords
Stress, Stress response pathways, Relapse, Emotions, Addictive behaviors, Hypothalamic-
pituitary-adrenocortical axis, Sympathetic-adrenal-medullary response, Addictive behaviors,
Cortisol
1 INTRODUCTION
The stress–addiction connection has been well established in the literature. The solid
foundation of research upon which the connection rests and multiple advances in the
fields of endocrinology, neuroimaging, computer science, and clinical practice have
43
44 CHAPTER 3 Stress psychobiology in the context of addiction medicine
resulted in several new avenues of study relevant to stress and addiction. In this
chapter, we will review the basic psychology and biology of the stress response.
From there, we will review how stress may be a vulnerability factor for substance
use initiation, maintenance of continued substance use and, finally, relapse following
an attempt to quit chronic substance abuse. In addition to stress as a vulnerability
factor, we will also review other moderators of the addiction cycle. We briefly
review some of the newer forms of appetitive or “addictive” behaviors including
gambling, sex, and excessive internet use. This review will conclude with a model
of stress and addiction.
1.1 DEFINITIONS
Stress is an elusive, often overused, concept. Although “stress” has become the com-
mon cold of the twenty-first century evoked to explain an ever increasing array of
modern maladies, in this review, we will refer to “stress” as the lived, psychological,
and phenomenological experience. In contrast, the “stress response” will be used to
describe the physiological and neurophysiological changes that accompany the
stress experience. A “stressor” refers to the circumstance, encounter, environment,
or situation that evokes both “stress” and a “stress response” in an individual or
organism.
As with the concept of stress, “addiction” is a highly complex behavioral phe-
nomenon involving multiple components including behavioral, emotional, cogni-
tive, and physiological systems. Of particular importance are the symptoms of
withdrawal, negative affect, and craving that accompany abstinence (both acute
and prolonged), and the high produced by the consumption of the addictive sub-
stance. While a variety of stressors external to the addiction process may facilitate
initial experimentation, chronic use, or relapse, the withdrawal and negative affect
that accompanies withdrawal are in themselves an aversive and stressful experience
(Kassel et al., 2007). Use in response to negative affect will result in negative rein-
forcement (removal of an aversive stimulus) which, in turn, increases the probability
of subsequent use and, if repeated, chronic use. Positive reinforcement stems from
the high or the pleasure experienced in response to use of an addictive substance. The
Diagnostic and Statistical Manual-IV (American Psychiatric Association, 2000)
defined addiction or substance dependence as a “maladaptive pattern of substance
use leading to clinically significant impairment or distress” (American Psychiatric
Association, 2000). The current DSM 5 (American Psychiatric Association, 2014)
has redefined the definition of addiction to include both substance abuse and depen-
dence that occur along a natural continuum from mild to severe. Qualifying
for a diagnosis under this new system the words “addiction” and “dependence”
are avoided in favor of the more broad substance use disorders.
If indeed stress is a critical factor at all stages of the addiction cycle from
experimentation, to maintenance of chronic use, and to relapse upon attempted
cessation, then we should see evidence of a stress effect at all levels of analysis
from the macro (behavior) to the micro (cellular, genetic, and molecular). We would
2 Stress response systems 45
expect there to be a convergence of evidence from an analysis of such domains as

behavior, cognition, emotion, and physiology, both peripheral and central. Given
the wide range of analyses and the highly complex nature of each domain, support
for this supposition will necessarily be multidisciplinary, varied in methodologies,
and incremental.
2 STRESS RESPONSE SYSTEMS

Early in the twentieth century stress was viewed as a nonspecific physiological re-
sponse to demands placed on a body. This nonspecific response was studied in an-
imals, and later humans, with particular emphasis on changes in either the adrenal
cortex (Hans Selye) or the medulla (Walter B. Cannon (Hinkle, 1987)). Both Selye
and Cannon were interested in not only the multisystemic effects of stress, but they
were also among the first to coin terms and concepts still in use in the study of stress.
2.1 SYMPATHETIC-ADRENAL-MEDULLARY AXIS

Walter B. Cannon was the first to characterize the acute stress response as the “flight
or fight” response, or the automatic behavioral reaction induced, or so it was be-
lieved, by the production of adrenalin (later termed epinephrine) by the adrenal me-
dulla of an organism when faced with a threatening situation or foe. While Cannon’s
research was limited to sympathectomized animal preparations, we now know the
sympathetic-adrenal-medullary (SAM) axis stimulates the production of neurotrans-
mitters norepinephrine (NE) and epinephrine (EPI). The locus coeruleus is dense
with catecholamine neurons, and activation of these neurons increases sympathetic
nervous system (SNS) activity which is propagated via sympathetic preganglion
neurons. Stimulation of these neurons in turn stimulates the adrenal medulla to
release NE and EPI into circulation. These neurotransmitters activate receptors such
as smooth and cardiac muscles, other endocrine glands, the immune system, and
adipose tissue.
The study of SAM functions and emotional states got its start with Cannon’s an-
imal studies in 1911, but it was not until technological advancements in the 1950s
that allowed for the detailed study of negative emotions and catecholamines in hu-
man urine. Since that time the physiological consequences of emotion-induced SNS
arousal have been extensively studied, in particular, the effects of negative emotions
on cardiovascular functions (Goldstein and Kopin, 2008; Martens et al., 2008). This
early work led to the supposition that different emotional states have different cat-
echolamine profiles (Goldstein and Kopin, 2008). Some of these early conceptual-
izations, such as the differential catecholamine profile for anger directed inward as
opposed to outward, continue to play a role in the study of stress and addiction
(al’Absi and Bongard, 2006; al’Absi et al., 2007).
2.2 HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

In addition to the SAM system, others have focused on the hypothalamic-pituitary-
adrenal (HPA) axis. Hans Selye, often referred to as the father of stress studies, out-
lined a series of stages through which the challenged individual (animal or human)
goes through when faced with prolonged stress. He called this the general adaptation
syndrome (GAS) which consists of alarm, resistance, and exhaustion. Selye identified
the adrenal cortex with its production of mineralocorticoids and glucocorticoids as the
key mediators of the stress response. In the alarm phase, the cascade of events begins
with the detection of a threat and the production of corticotropin-releasing factor
(CRF) and vasopressin from neurons in the paraventricular nucleus (PVN). This
CRF is transported from the median eminence of the hypothalamus to the anterior
pituitary where it stimulates the production of proopiomelanocortin (POMC). POMC,
a relatively large precursor protein, is enzymatically cleaved into beta-endorphin
(b-endorphin) and adrenocorticotropic hormone (ACTH). The ACTH enters into
peripheral circulation and stimulates the cortex of the adrenal gland to produce gluco-
corticoids (cortisol in humans, corticosterone in rodents). Selye’s resistance phase
occurs when an organism seeks to reduce or eradicate the source of the threat or stress
that initiated the GAS. In both humans and animals, a variety of physically and
psychologically demanding behaviors are elicited during this phase. Many of these
attempts to cope with or eliminate the stressor during the resistance phase are either
unsuccessful, or in the case of substance use in humans, harmful. When coping and
resistance fail, the glucocorticoid production persists due to failure of the negative
feedback regulation of the system until physiological and emotional exhaustion
occurs. Selye was among the first to study extensively the wide range of negative
physiological consequences of stress during the exhaustion phase, including thymic
atrophy, gastric and duodenal ulcers, and even death. Contemporary researchers have
documented important negative impacts of CRF and cortisol on neuronal morphology
and functions all along the developmental trajectory (Buss et al., 2012; Lupien et al.,
2009). The timing of glucocorticoid exposure during development is an important
predictor of CNS morphology impact and it has been proposed that early exposure
to glucocorticoids increases the risk of later emotional and behavioral problems
(Lupien et al., 2009). Glucocorticoid production in response to threat is not, however,
universal nor is it necessarily detrimental. Cortisol plays a critical role in multiple
adaptive body functions and the absence, as well as the overproduction, of cortisol
is a clinical condition requiring intervention and treatment (Allolio, 2015). Selye
was also the first to distinguish individual differences in stress reactivity which
included “distress” or negative reactions and “eustress” or positive reactions.
2.3 THE INTEGRATION OF THE STRESS RESPONSE

The HPA and SAM systems do not act in isolation. Instead, there is a highly complex
and dynamic CNS system of integration. This system can be simplified into several
basic components, one of which includes arousal. All stressful situations begin with
2 Stress response systems 47
heightened arousal which moderates the behavioral response to the stress. Neuro-
physiologically, this requires the coordinated efforts of hypothalamic CRF and locus
coeruleus-derived NE systems. For example, neurons project bidirectionally be-
tween CRF-producing hypothalamic periventricular nucleus neurons to the brain
stem areas rich in NE including the locus coeruleus. Neurochemical and pharmaco-
logical studies using agonists and antagonists for both CRF and NE further support
the tight interconnection between these two regions (Dunn et al., 2004).
This dynamic relationship between the PVN and locus coeruleus is, in turn, in
dynamic relationship with other brain regions implicated in the process of addiction.
For example, the hypothalamic PVN receives input directly or indirectly from mul-
tiple regions including the prefrontal cortex, lateral septum, amygdala, hippocampus,
and the bed nucleus of the stria terminalis (BNST; Herman et al., 2002). Thus,
upstream brain regions implicated in emotions (limbic: septum, amygdala), decision
making (prefrontal cortex), memory (hippocampus), and stress (BNST) all relay sig-
nals capable of modifying activity within the PVN. In addition to CRF, these circuits
have their own mediators which include other neuromodulators and neurotransmit-
ters such as glutamate, GABA, substance P, NPY, dopamine, endogenous opioids,
endocannabinoids (eCBs), and serotonin (Fride et al., 2009; Herman et al., 2004;
Korte et al., 1991). A complete overview of cortical neuromodulators and neuro-
transmitters is beyond the scope of this review, but the curious reader may find
the reviews by Kavalali or Wang and Lupica helpful (Kavalali, 2015; Wang and
Lupica, 2014).
Likewise, the locus coeruleus receives afferent projects from peripheral inputs
(e.g., vagal and somatosensory afferents), the brainstem and higher cortical regions
such as the amygdala, hypothalamus, and prefrontal cortex. In turn, the locus coer-
uleus sends projects widely throughout the cortex, limbic system, thalamus, and
hypothalamus and the brainstem and it has been shown to modulate prefrontal cortex
independent of hypothalamic inputs (Chandler et al., 2014). Its functional targets
include regions mediating sleep–wake cycles, neuroendocrine functioning (includ-
ing the HPA), and autonomic, motor, and sensory functions. As an integrator of
the stress response, the locus coeruleus and noradrenergic inputs regulate many
broad behaviors as sleep, arousal, neuropathology, cognition, and pain modulation
(Van Bockstaele and Valentino, 2013).
In addition to complex dynamics of CRF and NE systems, other complex, distrib-
uted networks in the brain help to regulate the stress response. These include
serotonergic, endogenous opioid, and eCB systems. There is some evidence that
the LC–NE system response to stress is moderated by both CRF and endogenous opi-
oids. Social stress in rats results in persistent decrease in LC activation which is
moderated by endogenous m-opioid receptor functioning (Chaijale et al., 2013;
Curtis et al., 2012). Serotonin, like CRF, is increased by a variety of stress paradigms,
CRF signaling, or electrical stimulation of the PVN and stimulation of serotonin, in
turn, heightens both the HPA axis and the SAM system (Kondo et al., 2015). Finally,
eCBs have recently been shown to moderate the stress response. For example, the
eCB system (Di Marzo et al., 2005) consists of two endogenous ligands, AEA
(N-arachidonylethanolamine anandamide) and 2-AG (2-arachidonoylglycerol).

Acute stress in humans leads to increased production and release of eCBs
(Dlugos et al., 2012). Likewise, eCBs may also act to regulate the stress-related
HPA axis activation (Hill and McEwen, 2010). The system is highly dynamic as
evident by the fact that CNS eCB signaling has been shown to regulate both the
activation and termination of stress through decreases in brain AEA and increases
in AG-1 (Steiner and Wotjak, 2008).
This overview suggests that the HPA and LC–NE systems are dynamically inter-
dependent and both systems, in turn, are affected by other stress-related systems
including serotonergic, endogenous opioid, and eCB systems. As we will see in sub-
sequent sections, each of these systems, in turn, moderate a variety of behaviors that
have been implicated or observed as a component of the addiction process.
2.4 COMMON PATHWAYS BETWEEN STRESS AND ADDICTION

There is evidence that, in many ways, the dynamic neurophysiology of the stress re-
sponse mirrors that of the neurophysiology evident in humans and animals who have
been chronically exposed to drugs of abuse. For example, both stress and addiction
share similar changes in behavior, similar neurophysiological changes in the HPA,
LC–NE, autonomic, and eCB systems, and similar risk profiles (sex, psychopathol-
ogy, etc.). Chronic social stress in animals and humans leads to increases in anxiety,
negative affect, and changes in sleep and eating (Adam and Epel, 2007; Akerstedt,
2006; Chida and Hamer, 2008), all of which are common in persistent substance
abuse. The same is true for disruptions in attention, concentration, memory, and de-
cision making (Het et al., 2005). From a neurophysiological perspective, there are
also many common pathways. As indicated above, both chronic social stress and
chronic exposure to drugs of abuse such as morphine leads to changes in LC–NE
functioning that appears to be dependent upon endogenous opioid functions
(Chaijale et al., 2013; Curtis et al., 2012). In general, though there is some variability
based on the chemistry of the abused substance, acute drug use also leads to increased
HPA and SNS functioning in much the same way as stress (al’Absi et al., 2008; Fox
et al., 2006; Hamidovic et al., 2010; Mick et al., 2013).
One common pathway that has received the most intense research attention is the
role of dopaminergic reward pathways in the brain. As stated above, drugs of abuse
heighten the activity of the HPA, SNS, and endogenous opioid systems in much
the same way as chronic stress. The behavioral effects are, in turn, moderated by
multiple neurobiological systems including the catecholamines: dopamine, NE,
and serotonin (Salamone and Correa, 2013). The HPA and dopaminergic systems
are interdependent (Boyson et al., 2014). Dopamine in particular has been linked
to the reward properties of drug use. For example, pharmacological studies have
shown that stress increases dopamine production via glucocorticoid receptor activa-
tion (Boyson et al., 2014). In particular, increased central CRF activity potentiates
N-methyl-D-aspartate receptor activity which, in turn, results in increased dopami-
nergic transmission (Marinelli, 2007). Support for the role of HPA activation in
3 Stress as a vulnerability factor 49
increasing dopaminergic activity has been evident in studies using a variety of meth-
odologies (Barrot et al., 2000; Graf et al., 2013). Through this research, critical CNS
reward pathways and structures have identified including the ventral tegmental area,
nucleus accumbens, and prefrontal cortex (Baik, 2013; Kringelbach et al., 2012;
Lawrence and Brooks, 2014).
In addition to the dopaminergic reward pathway, both stress and drugs of abuse
negatively impact the serotonergic pathway consisting of the raphe nucleus, striatum,
nucleus accumbens, and the entire neocortex. The effects of altered serotonergic
functioning are expressed as changes in mood, memory, sleep, and cognition; all
of which are evident in chronic stress states and drug abuse (Kirby et al., 2011;
Meerlo et al., 2008; Meneses, 2013).
3 STRESS AS A VULNERABILITY FACTOR FOR INITIATION

AND MAINTAINING SUBSTANCE ABUSE
3.1 DEVELOPMENTAL STUDIES IN ANIMALS
Evidence of developmental stress as a vulnerability factor has been provided for
nearly all substances of abuse, though this differs based on the timing of the stressor
(prenatal versus postnatal) and the developmental stage in which substance exposure
is tested. For example, maternal stress during gestation can be induced by a variety of
experimental paradigms including restraint stress, noise stress, and social stressors
using both rodents and nonhuman primates, each of which may produce different
outcomes (Nylander and Roman, 2013). This prenatal maternal stress leads to dis-
ruption in both basal and stress responsivity along multiple systems including the
HPA, dopamine, NE, acetylcholinergic, opioid, and eCB systems (Carboni et al.,
2010; Fride et al., 2009; Hausknecht et al., 2013). Neuroanatomical studies have
further verified that the ventral tegmental area, nucleus accumbens, and prefrontal
cortex show cellular and genetic changes consistent with the type of changes seen
in chronic substance use (Carboni et al., 2010; Hausknecht et al., 2013; Kippin
et al., 2008). Behaviorally, prenatally stressed offspring demonstrate an increased
likelihood of dysphoria and anxiety. When tested later in life for substance use
adoption, such prenatally stressed offspring more rapidly adopt a variety of abusive
substances including, among others, nicotine, cocaine, marijuana, alcohol, benzo-
diazepines, and amphetamines (Lakehayli et al., 2015; Reynaert et al., 2015;
Rokyta et al., 2008; Silvagni et al., 2008). Further, animals including rats and
nonhuman primates that are separated from their mother early in life demonstrate
HPA dysregulations, behavioral changes indicative of distress and persistent mood
disorder, and increased proclivity toward heightened use of addictive substances
(Brenhouse et al., 2013; Coplan et al., 2011). Some have suggested that prenatal
stress does not directly impact alcohol preference but instead alters the response
to alcohol consumption (Van Waes et al., 2011), though others do report that prenatal
stress affects preference for alcohol (Campbell et al., 2009).
3.2 DEVELOPMENTAL STUDIES IN HUMANS

Although limited due to ethical restrictions, there is cross-sectional and quasi-
experimental support for a similar effect of early life stress and addiction in humans.
For example, chronic stress, in particular stress during early development, increases
the risk for psychopathology during adulthood, and, in turn, both chronic stress and
psychopathology are risk factors for the initiation, maintenance, and relapse of drug
abuse (Brenhouse et al., 2013; Enoch, 2011; Lovallo, 2013). Adverse childhood
events (abuse, neglect, separation, and loss during childhood) are associated with
early onset of substance use and increased risk of addiction (Banducci et al.,
2014; Heron et al., 2013; Hyman et al., 2006; Mason and Spoth, 2012). This has been
shown via large epidemiological studies (Heron et al., 2013), studies of drug-
dependent patients, psychiatry patients or dual diagnosis patients (Banducci et al.,
2014; Brensilver et al., 2013; Evren et al., 2013; Hyman et al., 2006; Kim et al.,
2013; Walsh and Cawthon, 2014), and subsequent case follow-up studies of children
with officially documented abuse (Macleod et al., 2013).
The likely mechanisms of early stress and addiction potential, similar to the animal
research, include dysregulations of the HPA axis and endogenous opioid functions
(Dai et al., 2007; Gianoulakis et al., 2005). The offspring of substance using parents
demonstrate hyporesponsiveness of cortisol and b-endorphine in response to stress and
exaggerated b-endorphine in response to alcohol use (Mick et al., 2013). Significant
progress has also been made in identifying genetic vulnerability factors including
receptors for GABA A, dopamine r, acetylcholine, and serotonin (for review, see
Schuckit, 2014). Although as yet unclear, work with the dopamine and nicotinic
acetylcholine gene variants suggests an involvement of central reward systems while
the GABA and NPY gene variants suggest a direct or indirect involvement of affect
dysregulation as well. A full understanding of the complexity of multiple intercon-
nections between drug effect, reward, and affect is lacking.
4 STRESS AS A RISK FACTOR FOR RELAPSE

Once use becomes chronic and problematic, cessation or abstinence is often desired
but exceedingly difficult to achieve. For example, with tobacco smoking the success
rate following an attempted cessation is quite low with the majority (80%) relaps-
ing within the first month of abstinence. One common explanation for smoking
relapse is stress (Cohen and Lichtenstein, 1990). Smoking relapse due to psychoso-
cial stress moves faster than relapse due to other explanations such as alcohol, eating,
or drinking (Shiffman et al., 1996). Various physiological markers of stress predict
relapse. For example, smokers who demonstrate an attenuated sympathetic and
HPA stress response during the first 24 h of relapse have an increased risk of relapse
status at 4 weeks postquit (al’Absi, 2006; al’Absi et al., 2004, 2005; Ceballos and
al’Absi, 2006) as does heightened negative affect (al’Absi et al., 2004). Smokers
report significant craving, distress, anger, and physical symptoms during withdrawal
(Hughes and Hatsukami, 1986; Tiffany and Drobes, 1991). Likewise, craving or
5 Stress and behavioral addictions 51
distress-induced relapse is a powerful negative reinforcement for persistent smoking

(Ahmed and Koob, 2005). Although this experience is psychologically stressful, the
seemingly counterintuitive attenuated response of those who relapse appears to be
related, at least in part, to CRF (Erb, 2007). It is important to recall that acute exposure
to nicotine induces a rise in HPA activity which, when chronic, leads to elevation of
HPA function. In time this may trigger the HPA’s negative feedback loop, of which
glucocorticoids and the activation of the glucocorticoid receptors are the central driver.
In addition to the HPA axis, catecholamines and glutamate within the nucleus accum-
bens and prefrontal cortex are induced by drug cues, drug use, and/or stress. These
factors are also related to negative affect and, in turn, addiction, impulsivity, or poor
decision making (Naqvi and Bechara, 2010). Here, we see the convergence of the
experience of stress, either exogenous or specific to the withdrawal experience,
negative affect, and executive cognitive skills working in concert to enhance an
addict’s risk for relapse during a cessation attempt (see Fig. 1).
Although we began this section using nicotine addiction as an example, it is im-
portant to point out that stress and abnormal cortisol responses have also been linked
to relapse with other substances cessation attempts including cocaine, opiates, alco-
hol, amphetamines, and marijuana (Fox et al., 2013; Hamidovic et al., 2010; Higley
et al., 2011; Sinha, 2011). With some abuse substances such as heroin, however, the
cortisol response is elevated rather than attenuated, especially in response to drug
paraphernalia cues (Fatseas et al., 2011). Regardless of the direction of the HPA
changes, there is abundant evidence that drug use is related to dysregulation
of the HPA axis, perhaps in concert with dysregulation in the emotional regulation,
central reward, and executive function systems.
5 STRESS AND BEHAVIORAL ADDICTIONS

For the first time, gambling disorder was added to the DSM 5 in 2013 due to its clear
addictive behavior patterns (Hasin et al., 2013). If, as we have argued above, psycho-
logical stress is a key factor in the initiation, maintenance, and relapse for all addic-
tions, then it would stand to reason that there should be evidence of such a stress and
addiction relationship among all behavioral, emotional, cognitive, and physiological
parameters of stress specific to gambling. This is, indeed, the case for many of these
parameters. For example, reported psychosocial stresses such as divorce, marital
strife, and a history of childhood abuse are more prevalent in samples of pathological
gamblers (PGs) (Black et al., 2012). Higher life stress at the time of treatment is one
of the strongest predicts PG relapse at 4 months posttreatment (Gomes and Pascual-
Leone, 2014). Although baseline cortisol may not be elevated with gambling
disorder, there are negative correlations with the length of pathological gambling
and cortisol, total gambling dysfunction, and distress over gambling behavior
(Geisel et al., 2015). Further, gambling-related behaviors increase with experimental
induction of a stress state, though not with all types of stressors (Steinberg et al.,
2011). Early research indicates that stress physiology, as measured by the HPA,
and
and
and
and
—
FIGURE 1
A heuristic representation of the multiple roles of stress in the addiction process including
initiation, maintenance, and relapse is shown above. As described in the text, stress is a
vulnerability factor for both initiation and relapse, and dysregulation of the HPA axis and the
sympathetic nervous system work in concert to foster maintenance of addiction.
sympathetic, serotonergic, dopaminergic, and endogenous opioid systems, has been

linked to gambling behaviors, maintenance, and relapse (Blanchard et al., 2000;
Campbell-Meiklejohn et al., 2011; van den Bos et al., 2009). For PGs, basal circu-
lating NE, EPI, and dopamine are elevated and the act of gambling is an arousal state
(Meyer et al., 2004). In contrast to basal levels or gambling behaviors, the cortisol
response to gambling cues may be absent for PGs but not recreational gamblers
(Paris et al., 2010a,b). Finally, neuroimaging studies indicate that, like alcohol
addiction, pathological gambling is associated with abnormalities in the anterior
cingulate, ventral striatum, and prefrontal cortices (Koehler et al., 2013).
Other behaviors with addictive qualities (persistent and dysfunctional use or
behavior leading to clinically significant impairment or distress) include
6 Moderators of the stress effects on the addiction cycle 53
hypersexuality, internet use disorder, and noneating disordered excessive eating

(AKA “food addiction”). While each of these have not yet risen to the level of in-
clusion in the DSM 5 as a substance use disorder, there is some recognition that each
of these have in common an escalating pattern of use leading to dysfunction. Further,
early evidence exists of a link between these potential behavioral addictions (pur-
ported sex addiction and internet use disorder) and dopamine, self-reported stress,
or the HPA axis dysregulation (Farre et al., 2015; Hou et al., 2012). Finally, there
is currently a large debate on whether or not there is a “food addiction” or
“eating addiction” that is distinct from the traditional eating disorders of anorexia
or bulimia exists (Rogers and Smit, 2000). Although still quite controversial, those
who support the notion of a food addiction point to its vulnerability to stress and the
dopaminergic reward system as supporting evidence of its distinction from other
eating disorders (Adam and Epel, 2007; Volkow et al., 2013).
6 MODERATORS OF THE STRESS EFFECTS ON THE

ADDICTION CYCLE
6.1 SEX
Differential sex effects are seen across a broad range of addiction types and at all
many levels of analysis. It has been proposed that estrogen mediates many of the
sex differences observed related to drug cue sensitivity, stress responsivity, and
the negative reinforcement properties of drugs (Bobzean et al., 2014). In addition,
there are sex differences in the HPA, emotional, and cognitive dysregulations with
most, if not all, addictions (Hildebrandt and Greif, 2013). Within the area of nicotine
addiction and smoking, elevated salivary cortisol collected in women during the
early abstinence phase predicted quicker relapse while the opposite was true for
men (al’Absi et al., 2015). Such sex differences do not appear to be exclusive to drug
addiction. For example, behavioral addictions such as gambling are also notable for
sex differences in HPA functioning. Studies of the HPA axis show hypoarousal in
female and hyperarousal in male gamblers (Franco et al., 2010). While both genders
show an increase in cortisol in response to gambling cues (film), with actual or mock
gambling males show a linear negative relationship between cortisol levels a decline
in performance but females have shown a curvilinear relationship where very low
responding or high responding (cortisol) leads to declining performance (Paris
et al., 2010a,b; van den Bos et al., 2009). There are, however, many unanswered
questions, particularly on other sex-dependent cofactors and their effects on other
neuromodulators (for an excellent review, see Bisagno and Cadet, 2014).
6.2 GENETICS
The genetics and epigenetics of addiction have progressed in multiple areas in the
study of specific addictive substances (Levran et al., 2012; McCarthy et al., 2012;
Ponomarev, 2013) and the common behaviors span all addictions such as craving,
impulsivity, conditioning, or reward (Nestler, 2014). In parallel, the study of stress-

related genes or epigenetic factors has also made significant strides related to early
life stress and later risk of psychopathology (Lewis and Olive, 2014), stress across
the developmental spectrum, the regulation of the stress response, cognition, or re-
productive behavior (Gudsnuk and Champagne, 2012), social adversity and multiple
indicators of health and well-being, and stress in learning (Mifsud et al., 2011).
In contrast, limited studies have simultaneously examined the specific interaction
between stress and addiction. Notable exceptions include the study of transcription
factors such as Nur which is capable of acting as intermediate-early genes (Campos-
Melo et al., 2013), nuclear factor kappa-B (NFkB) induction of innate immune genes
(Crews et al., 2011), and cAMP response element-binding protein (CREB) target
genes, specifically those that regulate brain-derived neurotrophic factor, CRF, and
dynorphin (Briand and Blendy, 2010). For example, both stress and drug abuse in-
crease NFkB transcription results in increases in brain inflammatory mediators
which, in turn, have been linked to widespread and persistent alterations in behav-
ioral factors reflective of the neurobiology of addiction such as frontal lobe excitabi-
lity, negative affect, behavioral flexibility, and loss of behavioral control (Crews
et al., 2011). Animal work has shown that Nur transcription factors are activated
by stress and that drugs of abuse may induce dopamine- and glutamate-dependent
Nur transcription in the striatum and nucleus accumbens, both of which display tol-
erance and sensitization (Campos-Melo et al., 2013). It has been proposed that CREB
may be a critical link controlling the link between reward circuits and the HPA axis
and it may therefore help to explain, in part, the complex interaction between stress
and drug abuse (Briand and Blendy, 2010). Finally, variants to the m-opioid receptors
have been identified as a potential gene mediating food addiction via reward, crav-
ing, and preference. Work in humans has shown that individuals who are AA or GG
homozygous for the A118G m-opioid receptor gene have enhanced hedonic respon-
siveness relative to heterozygous (GA) individuals which, in turn, predicts greater
propensity toward food-related addictive behaviors (Davis and Loxton, 2014).
7 DISCUSSION
As reviewed above, research on nicotine and alcohol addiction clearly indicates that
there are important sex differences in the pattern of addictive behaviors, relapse, and
stress neurobiology. There is a need for further clarity on sex differences in other
areas of addiction as well, particularly the newer areas of study such as gambling
disorder, internet use disorder, and hypersexuality. Much of this literature includes
males only and those that do include women fail to analyze for sex differences. Like-
wise, there are very few studies with non-Caucasian minority groups.
Some studies involving a direct comparison of addiction types have shown that
not all stressors affect addictions equally. For example, controllable and uncont-
rollable noise stress increase the desire for alcohol equally across alcoholics,
PGs, dually diagnosed participants, and controls while only uncontrollable noise
References 55
increased the desire to gamble selectively within those with a history of pathological
gambling (Steinberg et al., 2011). How stressor characteristics interact with genetic
vulnerability is, as yet, understudied. Thus, further studies of the gene by environ-
ment interaction specific to stress and addiction are needed. Finally, further study
of stress resilience and coping will be important for informing future intervention
research.
8 CONCLUSION
The stress response has been shown to increase risk of initiation, maintenance, and
relapse of a variety of addictions. Evidence was presented in support of this proposal
utilizing all levels of analysis from the macro- (cross-sectional, population research)
to the micro-level (molecular, genetic, epigenetic research). The study of reward
systems in the brain and their interactions with HPA, sympathetic, eCB, and other
systems has taught us a great deal about the relationship between stress and addic-
tion. We propose the psychological stress and the biological stress response acts to
moderate the probability of initiation, maintenance, and relapse (see Fig. 1). As an
individual encounters stress-inducing environments, there are individual differences
that help to determine whether there is increased (high stress, right-hand path on
Fig. 1) or decreased (low stress, left-hand path on Fig. 1) probability of problematic
substance use. There are, however, other brain systems and moderators to explore. In
particular, we have only just begun to understand the gene by environment interac-
tions that occur within the context of stress and addiction. Likewise, there are a host
of behavioral, neuroendocrine, and cognitive differences between men and women
that have yet to be explored as potential moderators capable of accounting for sex
differences in stress and addiction. Finally, funding sources and the public are in-
creasingly demanding of reliable and efficient interventions, particularly in light
of the high treatment failure rates and the role that stress plays in relapse. To address
this gap future treatment-specific work, whether they include pharmacological or be-
havioral interventions, could benefit from further investigation of stress resilience.
REFERENCES
Adam, T.C., Epel, E.S., 2007. Stress, eating and the reward system. Physiol. Behav.
91, 449–458.
Ahmed, S.H., Koob, G.F., 2005. Transition to drug addiction: a negative reinforcement model
based on an allostatic decrease in reward function. Psychopharmacology (Berl)
180, 473–490.
Akerstedt, T., 2006. Psychosocial stress and impaired sleep. Scand. J. Work Environ. Health
32, 493–501.
al’Absi, M., 2006. Hypothalamic-pituitary-adrenocortical responses to psychological stress
and risk for smoking relapse. Int. J. Psychophysiol. 59, 218–227.
al’Absi, M., Bongard, S., 2006. Neuroendocrine and behavioral mechanisms mediating the
relationship between anger expression and cardiovascular risk: assessment considerations
and improvements. J. Behav. Med. 29, 573–591.
al’Absi, M., Hatsukami, D., Davis, G.L., Wittmers, L.E., 2004. Prospective examination of
effects of smoking abstinence on cortisol and withdrawal symptoms as predictors of early
smoking relapse. Drug Alcohol Depend. 73, 267–278.
al’Absi, M., Hatsukami, D., Davis, G.L., 2005. Attenuated adrenocorticotropic responses to
psychological stress are associated with early smoking relapse. Psychopharmacology
(Berl) 181, 107–117.
al’Absi, M., Carr, S.B., Bongard, S., 2007. Anger and psychobiological changes during smok-
ing abstinence and in response to acute stress: prediction of smoking relapse. Int. J. Psy-
chophysiol. 66, 109–115.
al’Absi, M., Wittmers, L.E., Hatsukami, D., Westra, R., 2008. Blunted opiate modulation of
hypothalamic-pituitary-adrenocortical activity in men and women who smoke. Psycho-
som. Med. 70, 928–935.
al’Absi, M., Nakajima, M., Allen, S., Lemieux, A., Hatsukami, D., 2015. Sex differences in
hormonal responses to stress and smoking relapse: a prospective examination. Nicotine
Tob. Res. 17, 382–389.
Allolio, B., 2015. Extensive expertise in endocrinology. Adrenal crisis. Eur. J. Endocrinol.
172, R115–R124.
American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disor-
ders, fourth ed. American Psychiatric Association, Washington, DC, text revision.
ders. American Psychiatric Association, Arlington, VA.
Baik, J.H., 2013. Dopamine signaling in reward-related behaviors. Front. Neural Circuits
7, 152.
Banducci, A.N., Hoffman, E.M., Lejuez, C.W., Koenen, K.C., 2014. The impact of childhood
abuse on inpatient substance users: specific links with risky sex, aggression, and emotion
dysregulation. Child Abuse Negl. 38, 928–938.
Barrot, M., Marinelli, M., Abrous, D.N., Rouge-Pont, F., Le Moal, M., Piazza, P.V., 2000. The
dopaminergic hyper-responsiveness of the shell of the nucleus accumbens is hormone-
dependent. Eur. J. Neurosci. 12, 973–979.
Bisagno, V., Cadet, J.L., 2014. Stress, sex, and addiction: potential roles of corticotropin-
releasing factor, oxytocin, and arginine-vasopressin. Behav. Pharmacol. 25, 445–457.
Black, D.W., Shaw, M.C., McCormick, B.A., Allen, J., 2012. Marital status, childhood mal-
treatment, and family dysfunction: a controlled study of pathological gambling. J. Clin.
Psychiatry 73, 1293–1297.
Blanchard, E.B., Wulfert, E., Freidenberg, B.M., Malta, L.S., 2000. Psychophysiological
assessment of compulsive gamblers’ arousal to gambling cues: a pilot study. Appl.
Psychophysiol. Biofeedback 25, 155–165.
Bobzean, S.A., DeNobrega, A.K., Perrotti, L.I., 2014. Sex differences in the neurobiology of
drug addiction. Exp. Neurol. 259, 64–74.
Boyson, C.O., Holly, E.N., Shimamoto, A., Albrechet-Souza, L., Weiner, L.A., DeBold, J.F.,
Miczek, K.A., 2014. Social stress and CRF-dopamine interactions in the VTA: role in
long-term escalation of cocaine self-administration. J. Neurosci. 34, 6659–6667.
Brenhouse, H.C., Lukkes, J.L., Andersen, S.L., 2013. Early life adversity alters the
developmental profiles of addiction-related prefrontal cortex circuitry. Brain Sci.
3, 143–158.
References 57
Brensilver, M., Heinzerling, K.G., Swanson, A.N., Telesca, D., Furst, B.A., Shoptaw, S.J.,
2013. Cigarette smoking as a target for potentiating outcomes for methamphetamine abuse
treatment. Drug Alcohol Rev. 32, 96–99.
Briand, L.A., Blendy, J.A., 2010. Molecular and genetic substrates linking stress and addic-
tion. Brain Res. 1314, 219–234.
Buss, C., Davis, E.P., Shahbaba, B., Pruessner, J.C., Head, K., Sandman, C.A., 2012. Maternal
cortisol over the course of pregnancy and subsequent child amygdala and hippocampus
volumes and affective problems. Proc. Natl. Acad. Sci. USA 109, E1312–E1319.
Campbell, J.C., Szumlinski, K.K., Kippin, T.E., 2009. Contribution of early environmental
stress to alcoholism vulnerability. Alcohol 43, 547–554.
Campbell-Meiklejohn, D., Wakeley, J., Herbert, V., Cook, J., Scollo, P., Ray, M.K.,
Selvaraj, S., Passingham, R.E., Cowen, P., Rogers, R.D., 2011. Serotonin and dopamine
play complementary roles in gambling to recover losses. Neuropsychopharmacology
36, 402–410.
Campos-Melo, D., Galleguillos, D., Sanchez, N., Gysling, K., Andres, M.E., 2013. Nur tran-
scription factors in stress and addiction. Front. Mol. Neurosci. 6, 44.
Carboni, E., Barros, V.G., Ibba, M., Silvagni, A., Mura, C., Antonelli, M.C., 2010. Prenatal
restraint stress: an in vivo microdialysis study on catecholamine release in the rat prefron-
tal cortex. Neuroscience 168, 156–166.
Ceballos, N.A., al’Absi, M., 2006. Dehydroepiandrosterone sulfate, cortisol, mood state and
smoking cessation: relationship to relapse status at 4-week follow-up. Pharmacol. Bio-
chem. Behav. 85, 23–28.
Chaijale, N.N., Curtis, A.L., Wood, S.K., Zhang, X.Y., Bhatnagar, S., Reyes, B.A., Van
Bockstaele, E.J., Valentino, R.J., 2013. Social stress engages opioid regulation of locus
coeruleus norepinephrine neurons and induces a state of cellular and physical opiate
dependence. Neuropsychopharmacology 38, 1833–1843.
Chandler, D.J., Waterhouse, B.D., Gao, W.J., 2014. New perspectives on catecholaminergic
regulation of executive circuits: evidence for independent modulation of prefrontal functions
by midbrain dopaminergic and noradrenergic neurons. Front. Neural Circuits 8, 53.
Chida, Y., Hamer, M., 2008. Chronic psychosocial factors and acute physiological responses
to laboratory-induced stress in healthy populations: a quantitative review of 30 years of
investigations. Psychol. Bull. 134, 829–885.
Cohen, S., Lichtenstein, E., 1990. Perceived stress, quitting smoking, and smoking relapse.
Health Psychol. 9, 466–478.
Coplan, J.D., Abdallah, C.G., Kaufman, J., Gelernter, J., Smith, E.L., Perera, T.D., Dwork, A.J.,
Kaffman, A., Gorman, J.M., Rosenblum, L.A., Owens, M.J., Nemeroff, C.B., 2011. Early-
life stress, corticotropin-releasing factor, and serotonin transporter gene: a pilot study.
Psychoneuroendocrinology 36, 289–293.
Crews, F.T., Zou, J., Qin, L., 2011. Induction of innate immune genes in brain create the neu-
robiology of addiction. Brain Behav. Immun. 25 (Suppl. 1), S4–S12.
Curtis, A.L., Leiser, S.C., Snyder, K., Valentino, R.J., 2012. Predator stress engages
corticotropin-releasing factor and opioid systems to alter the operating mode of locus coer-
uleus norepinephrine neurons. Neuropharmacology 62, 1737–1745.
Dai, X., Thavundayil, J., Santella, S., Gianoulakis, C., 2007. Response of the HPA-axis to
alcohol and stress as a function of alcohol dependence and family history of alcoholism.
Davis, C., Loxton, N.J., 2014. A psycho-genetic study of hedonic responsiveness in relation to
“food addiction” Nutrients 6, 4338–4353.
Di Marzo, V., De Petrocellis, L., Bisogno, T., 2005. The biosynthesis, fate and pharmacolo-
gical properties of endocannabinoids. Handb. Exp. Pharmacol. 168, 147–185.
Dlugos, A., Childs, E., Stuhr, K.L., Hillard, C.J., de Wit, H., 2012. Acute stress increases cir-
culating anandamide and other N-acylethanolamines in healthy humans.
Neuropsychopharmacology 37, 2416–2427.
Dunn, A.J., Swiergiel, A.H., Palamarchouk, V., 2004. Brain circuits involved in corticotropin-
releasing factor-norepinephrine interactions during stress. Ann. N. Y. Acad. Sci.
1018, 25–34.
Enoch, M.A., 2011. The role of early life stress as a predictor for alcohol and drug dependence.
Psychopharmacology (Berl) 214, 17–31.
Erb, S., 2007. Neurobiology of stress and risk for relapse. In: al’Absi, M. (Ed.), Stress and
Addiction: Biological and Psychological Mechanisms. Academic Press/Elsevier,
London, pp. 147–169.
Evren, C., Cinar, O., Evren, B., Ulku, M., Karabulut, V., Umut, G., 2013. The mediator roles of
trait anxiety, hostility, and impulsivity in the association between childhood trauma and
dissociation in male substance-dependent inpatients. Compr. Psychiatry 54, 158–166.
Farre, J.M., Fernandez-Aranda, F., Granero, R., Aragay, N., Mallorqui-Bague, N., Ferrer, V.,
More, A., Bouman, W.P., Arcelus, J., Savvidou, L.G., Penelo, E., Aymami, M.N., Gomez-
Pena, M., Gunnard, K., Romaguera, A., Menchon, J.M., Valles, V., Jimenez-Murcia, S.,
2015. Sex addiction and gambling disorder: similarities and differences. Compr. Psychi-
atry 56, 59–68.
Fatseas, M., Denis, C., Massida, Z., Verger, M., Franques-Reneric, P., Auriacombe, M., 2011.
Cue-induced reactivity, cortisol response and substance use outcome in treated heroin de-
pendent individuals. Biol. Psychiatr. 70 (8), 720–727.
Fox, H.C., Garcia Jr., M., Kemp, K., Milivojevic, V., Kreek, M.J., Sinha, R., 2006. Gender
differences in cardiovascular and corticoadrenal response to stress and drug cues in
cocaine dependent individuals. Psychopharmacology (Berl) 185, 348–357.
Fox, H.C., Tuit, K.L., Sinha, R., 2013. Stress system changes associated with marijuana
dependence may increase craving for alcohol and cocaine. Hum. Psychopharmacol.
28, 40–53.
Franco, C., Paris, J., Wulfert, E., Frye, C., 2010. Male gamblers have significantly greater sal-
ivary cortisol before and after betting on a horse race, than do female gamblers. Physiol.
Behav. 99, 225–229.
Fride, E., Gobshtis, N., Dahan, H., Weller, A., Giuffrida, A., Ben-Shabat, S., 2009. The endo-
cannabinoid system during development: emphasis on perinatal events and delayed
effects. Vitam. Horm. 81, 139–158.
Geisel, O., Panneck, P., Hellweg, R., Wiedemann, K., Muller, C.A., 2015. Hypothalamic-
pituitary-adrenal axis activity in patients with pathological gambling and internet use dis-
order. Psychiatry Res. 226, 97–102.
Gianoulakis, C., Dai, X., Thavundayil, J., Brown, T., 2005. Levels and circadian rhythmicity
of plasma ACTH, cortisol, and beta-endorphin as a function of family history of alcohol-
ism. Psychopharmacology (Berl) 181, 437–444.
Goldstein, D.S., Kopin, I.J., 2008. Adrenomedullary, adrenocortical, and sympathoneural
responses to stressors: a meta-analysis. Endocr. Regul. 42, 111–119.
Gomes, K., Pascual-Leone, A., 2014. A resource model of change: client factors that influence
problem gambling treatment outcomes. J. Gambl. Stud. Epub ahead of print, PMID:
25112220.
References 59
Graf, E.N., Wheeler, R.A., Baker, D.A., Ebben, A.L., Hill, J.E., McReynolds, J.R.,
Robble, M.A., Vranjkovic, O., Wheeler, D.S., Mantsch, J.R., Gasser, P.J., 2013. Cortico-
sterone acts in the nucleus accumbens to enhance dopamine signaling and potentiate re-
instatement of cocaine seeking. J. Neurosci. 33, 11800–11810.
Gudsnuk, K., Champagne, F.A., 2012. Epigenetic influence of stress and the social environ-
ment. ILAR J. 53, 279–288.
Hamidovic, A., Childs, E., Conrad, M., King, A., de Wit, H., 2010. Stress-induced changes in
mood and cortisol release predict mood effects of amphetamine. Drug Alcohol Depend.
109, 175–180.
Hasin, D.S., O’Brien, C.P., Auriacombe, M., Borges, G., Bucholz, K., Budney, A.,
Compton, W.M., Crowley, T., Ling, W., Petry, N.M., Schuckit, M., Grant, B.F., 2013.
DSM-5 criteria for substance use disorders: recommendations and rationale. Am. J.
Hausknecht, K., Haj-Dahmane, S., Shen, R.Y., 2013. Prenatal stress exposure increases the
excitation of dopamine neurons in the ventral tegmental area and alters their responses
to psychostimulants. Neuropsychopharmacology 38, 293–301.
Herman, J.P., Tasker, J.G., Ziegler, D.R., Cullinan, W.E., 2002. Local circuit regulation
of paraventricular nucleus stress integration: glutamate-GABA connections. Pharmacol.
Biochem. Behav. 71, 457–468.
Herman, J.P., Mueller, N.K., Figueiredo, H., 2004. Role of GABA and glutamate circuitry in
hypothalamo-pituitary-adrenocortical stress integration. Ann. N. Y. Acad. Sci. 1018, 35–45.
Heron, J., Barker, E.D., Joinson, C., Lewis, G., Hickman, M., Munafo, M., Macleod, J., 2013.
Childhood conduct disorder trajectories, prior risk factors and cannabis use at age 16: birth
cohort study. Addiction 108, 2129–2138.
Het, S., Ramlow, G., Wolf, O.T., 2005. A meta-analytic review of the effects of acute cortisol
administration on human memory. Psychoneuroendocrinology 30, 771–784.
Higley, A.E., Crane, N.A., Spadoni, A.D., Quello, S.B., Goodell, V., Mason, B.J., 2011. Crav-
ing in response to stress induction in a human laboratory paradigm predicts treatment
outcome in alcohol-dependent individuals. Psychopharmacology (Berl) 218, 121–129.
Hildebrandt, T., Greif, R., 2013. Stress and addiction. Psychoneuroendocrinology
38, 1923–1927.
Hill, M.N., McEwen, B.S., 2010. Involvement of the endocannabinoid system in the neuro-
behavioural effects of stress and glucocorticoids. Prog. Neuropsychopharmacol. Biol.
Hinkle Jr., L.E., 1987. Stress and disease: the concept after 50 years. Soc. Sci. Med.
25, 561–566.
Hou, H., Jia, S., Hu, S., Fan, R., Sun, W., Sun, T., Zhang, H., 2012. Reduced striatal dopamine
transporters in people with internet addiction disorder. J. Biomed. Biotechnol.
2012, 854524.
Hughes, J.R., Hatsukami, D., 1986. Signs and symptoms of tobacco withdrawal. Arch. Gen.
Hyman, S.M., Garcia, M., Sinha, R., 2006. Gender specific associations between types of
childhood maltreatment and the onset, escalation and severity of substance use in cocaine
dependent adults. Am. J. Drug Alcohol Abuse 32, 655–664.
Kassel, J.D., Veilleux, J.C., Wardle, M.C., Yates, M.C., Greenstein, J.E., Evatt, D.P.,
Roesch, L.L., 2007. Negative affect and addiction. In: al’Absi, M. (Ed.), Stress and
Addiction. Academic Press, London, pp. 171–190.
Kavalali, E.T., 2015. The mechanisms and functions of spontaneous neurotransmitter release.
Nat. Rev. Neurosci. 16, 5–16.
Kim, S.W., Kang, H.J., Kim, S.Y., Kim, J.M., Yoon, J.S., Jung, S.W., Lee, M.S., Yim, H.W.,
Jun, T.Y., 2013. Impact of childhood adversity on the course and suicidality of depressive
disorders: the CRESCEND study. Depress. Anxiety 30, 965–974.
Kippin, T.E., Szumlinski, K.K., Kapasova, Z., Rezner, B., See, R.E., 2008. Prenatal stress
enhances responsiveness to cocaine. Neuropsychopharmacology 33, 769–782.
Kirby, L.G., Zeeb, F.D., Winstanley, C.A., 2011. Contributions of serotonin in addiction
vulnerability. Neuropharmacology 61, 421–432.
Koehler, S., Ovadia-Caro, S., van der Meer, E., Villringer, A., Heinz, A., Romanczuk-Seiferth,
N., Margulies, D.S., 2013. Increased functional connectivity between prefrontal cortex and
reward system in pathological gambling. PLoS One 8, e84565.
Kondo, F., Tachi, M., Gosho, M., Fukayama, M., Yoshikawa, K., Okada, S., 2015. Changes
in hypothalamic neurotransmitter and prostanoid levels in response to NMDA, CRF, and
GLP-1 stimulation. Anal. Bioanal. Chem. 407, 5261–5272. doi:http://dx.doi.org/10.1007/
s00216-015-8496-6. PMID:25633219.
Korte, S.M., Van Duin, S., Bouws, G.A., Koolhaas, J.M., Bohus, B., 1991. Involvement of
hypothalamic serotonin in activation of the sympathoadrenomedullary system and
hypothalamo-pituitary-adrenocortical axis in male Wistar rats. Eur. J. Pharmacol.
197, 225–228.
Kringelbach, M.L., Stein, A., van Hartevelt, T.J., 2012. The functional human neuroanatomy
of food pleasure cycles. Physiol. Behav. 106, 307–316.
Lakehayli, S., Said, N., Battas, O., Hakkou, F., Tazi, A., 2015. Prenatal stress alters sensitivity
to benzodiazepines in adult rats. Neurosci. Lett. 591, 187–191.
Lawrence, A.D., Brooks, D.J., 2014. Ventral striatal dopamine synthesis capacity is associated
with individual differences in behavioral disinhibition. Front. Behav. Neurosci. 8, 86.
Levran, O., Yuferov, V., Kreek, M.J., 2012. The genetics of the opioid system and specific
drug addictions. Hum. Genet. 131, 823–842.
Lewis, C.R., Olive, M.F., 2014. Early-life stress interactions with the epigenome: potential
mechanisms driving vulnerability toward psychiatric illness. Behav. Pharmacol.
25, 341–351.
Lovallo, W.R., 2013. Early life adversity reduces stress reactivity and enhances impulsive be-
havior: implications for health behaviors. Int. J. Psychophysiol. 90, 8–16.
Lupien, S.J., McEwen, B.S., Gunnar, M.R., Heim, C., 2009. Effects of stress throughout the
lifespan on the brain, behaviour and cognition. Nat. Rev. Neurosci. 10, 434–445.
Macleod, J., Hickman, M., Jones, H.E., Copeland, L., McKenzie, J., De Angelis, D., Kimber, J.,
Robertson, J.R., 2013. Early life influences on the risk of injecting drug use: case control
study based on the Edinburgh Addiction Cohort. Addiction 108, 743–750.
Marinelli, M., 2007. Dopaminergic reward pathways and effects of stress. In: Al’Absi, M.
(Ed.), Stress and Addiction: Biological and Psychological Mechanisms. Elsevier,
San Diego, CA, pp. 41–83.
Martens, A., Greenberg, J., Allen, J.J., 2008. Self-esteem and autonomic physiology: parallels
between self-esteem and cardiac vagal tone as buffers of threat. Pers. Soc. Psychol. Rev.
12, 370–389.
Mason, W.A., Spoth, R.L., 2012. Sequence of alcohol involvement from early onset to young
adult alcohol abuse: differential predictors and moderation by family-focused preventive
intervention. Addiction 107, 2137–2148.
References 61
McCarthy, D.M., Brown, A.N., Bhide, P.G., 2012. Regulation of BDNF expression by
cocaine. Yale J. Biol. Med. 85, 437–446.
Meerlo, P., Sgoifo, A., Suchecki, D., 2008. Restricted and disrupted sleep: effects on auto-
nomic function, neuroendocrine stress systems and stress responsivity. Sleep Med. Rev.
12, 197–210.
Meneses, A., 2013. 5-HT systems: emergent targets for memory formation and memory alter-
ations. Rev. Neurosci. 24, 629–664.
Meyer, G., Schwertfeger, J., Exton, M.S., Janssen, O.E., Knapp, W., Stadler, M.A.,
Schedlowski, M., Kruger, T.H., 2004. Neuroendocrine response to casino gambling in
problem gamblers. Psychoneuroendocrinology 29, 1272–1280.
Mick, I., Spring, K., Uhr, M., Zimmermann, U.S., 2013. Alcohol administration attenuates
hypothalamic-pituitary-adrenal (HPA) activity in healthy men at low genetic risk for al-
coholism, but not in high-risk subjects. Addict. Biol. 18, 863–871.
Mifsud, K.R., Gutierrez-Mecinas, M., Trollope, A.F., Collins, A., Saunderson, E.A., Reul, J.M.,
2011. Epigenetic mechanisms in stress and adaptation. Brain Behav. Immun.
25, 1305–1315.
Naqvi, N.H., Bechara, A., 2010. The insula and drug addiction: an interoceptive view of plea-
sure, urges, and decision-making. Brain Struct. Funct. 214, 435–450.
Nestler, E.J., 2014. Epigenetic mechanisms of drug addiction. Neuropharmacology 76 (Pt. B),
259–268.
Nylander, I., Roman, E., 2013. Is the rodent maternal separation model a valid and effective
model for studies on the early-life impact on ethanol consumption? Psychopharmacology
(Berl) 229, 555–569.
Paris, J.J., Franco, C., Sodano, R., Freidenberg, B., Gordis, E., Anderson, D.A., Forsyth, J.P.,
Wulfert, E., Frye, C.A., 2010a. Sex differences in salivary cortisol in response to acute
stressors among healthy participants, in recreational or pathological gamblers, and in those
with posttraumatic stress disorder. Horm. Behav. 57, 35–45.
Paris, J.J., Franco, C., Sodano, R., Frye, C.A., Wulfert, E., 2010b. Gambling pathology is as-
sociated with dampened cortisol response among men and women. Physiol. Behav.
99, 230–233.
Ponomarev, I., 2013. Epigenetic control of gene expression in the alcoholic brain. Alcohol
Res. 35, 69–76.
Reynaert, M.L., Marrocco, J., Gatta, E., Mairesse, J., Van Camp, G., Fagioli, F., Maccari, S.,
Nicoletti, F., Morley-Fletcher, S., 2015. A self-medication hypothesis for increased vul-
nerability to drug abuse in prenatally restraint stressed rats. Adv. Neurobiol. 10, 101–120.
Rogers, P.J., Smit, H.J., 2000. Food craving and food “addiction”: a critical review of the ev-
idence from a biopsychosocial perspective. Pharmacol. Biochem. Behav. 66, 3–14.
Rokyta, R., Yamamotova, A., Slamberova, R., Franek, M., Vaculin, S., Hruba, L.,
Schutova, B., Pometlova, M., 2008. Prenatal and perinatal factors influencing nociception,
addiction and behavior during ontogenetic development. Physiol. Res. 57 (Suppl. 3),
S79–S88.
Salamone, J.D., Correa, M., 2013. Dopamine and food addiction: lexicon badly needed. Biol.
Psychiatry 73, e15–e24.
Schuckit, M.A., 2014. A brief history of research on the genetics of alcohol and other drug use
disorders. J. Stud. Alcohol Drugs Suppl. 75 (Suppl. 17), 59–67.
Shiffman, S., Paty, J.A., Gnys, M., Kassel, J.A., Hickcox, M., 1996. First lapses to smoking:
within-subjects analysis of real-time reports. J. Consult. Clin. Psychol. 64, 366–379.
Silvagni, A., Barros, V.G., Mura, C., Antonelli, M.C., Carboni, E., 2008. Prenatal restraint
stress differentially modifies basal and stimulated dopamine and noradrenaline release
in the nucleus accumbens shell: an ‘in vivo’ microdialysis study in adolescent and young
adult rats. Eur. J. Neurosci. 28, 744–758.
Sinha, R., 2011. New findings on biological factors predicting addiction relapse vulnerability.
Curr. Psychiatry Rep. 13, 398–405.
Steinberg, L., Tremblay, A.M., Zack, M., Busto, U.E., Zawertailo, L.A., 2011. Effects of stress
and alcohol cues in men with and without problem gambling and alcohol use disorder.
Drug Alcohol Depend. 119, 46–55.
Steiner, M.A., Wotjak, C.T., 2008. Role of the endocannabinoid system in regulation of the
hypothalamic-pituitary-adrenocortical axis. Prog. Brain Res. 170, 397–432.
Tiffany, S.T., Drobes, D.J., 1991. The development and initial validation of a questionnaire on
smoking urges. Br. J. Addict. 86, 1467–1476.
Van Bockstaele, E.J., Valentino, R.J., 2013. Neuropeptide regulation of the locus coeruleus
and opiate-induced plasticity of stress responses. In: Eiden, L.E. (Ed.), New Era of Cat-
echolamines in the Laboratory and Clinic, vol. 68. Elsevier, San Diego, CA, pp. 405–420.
van den Bos, R., Harteveld, M., Stoop, H., 2009. Stress and decision-making in humans: per-
formance is related to cortisol reactivity, albeit differently in men and women.
Van Waes, V., Enache, M., Berton, O., Vinner, E., Lhermitte, M., Maccari, S.,
Darnaudery, M., 2011. Effect of prenatal stress on alcohol preference and sensitivity to
chronic alcohol exposure in male rats. Psychopharmacology (Berl) 214, 197–208.
Volkow, N.D., Wang, G.J., Tomasi, D., Baler, R.D., 2013. The addictive dimensionality of
obesity. Biol. Psychiatry 73, 811–818.
Walsh, E.G., Cawthon, S.W., 2014. The mediating role of depressive symptoms in the rela-
tionship between adverse childhood experiences and smoking. Addict. Behav.
39, 1471–1476.
Wang, H., Lupica, C.R., 2014. Release of endogenous cannabinoids from ventral tegmental
area dopamine neurons and the modulation of synaptic processes. Prog. Neuropsychophar-
macol. Biol. Psychiatry 52, 24–27.
CHAPTER
Reinforcement principles for

addiction medicine; from
recreational drug use to
psychiatric disorder
4
Scott Edwards1
Department of Physiology, Alcohol and Drug Abuse Center of Excellence, Neuroscience Center of
Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA
1
Corresponding author: Tel.: +1-619-2413380; Fax: +1-504-5686158,
Abstract
The transition from recreational drug use to addiction can be conceptualized as a pathological
timeline whereby the psychological mechanisms responsible for disordered drug use evolve
from positive reinforcement to favor elements of negative reinforcement. Abused substances
(ranging from alcohol to psychostimulants) are initially ingested at regular occasions accord-
ing to their positive reinforcing properties. Importantly, repeated exposure to rewarding sub-
stances sets off a chain of secondary reinforcing events, whereby cues and contexts associated
with drug use may themselves become reinforcing and thereby contribute to the continued use
and possible abuse of the substance(s) of choice. Indeed, the powerful reinforcing efficacy of
certain drugs may eclipse that of competing social rewards (such as career and family) and lead
to an aberrant narrowing of behavioral repertoire. In certain vulnerable individuals, escalation
of drug use over time is thought to drive specific molecular neuroadaptations that foster the
development of addiction. Research has identified neurobiological elements of altered rein-
forcement following excessive drug use that comprise within-circuit and between-circuit neu-
roadaptations, both of which contribute to addiction. Central to this process is the eventual
potentiation of negative reinforcement mechanisms that may represent the final definitive cri-
terion locking vulnerable individuals into a persistent state of addiction. Targeting the neural
substrates of reinforcement likely represents our best chances for therapeutic intervention for
this devastating disease.
Keywords
Addiction, Alcoholism, Amygdala, Dopamine, Nucleus accumbens, Reward, Reinforcement,
Self-administration, Substance use disorder

63
64 CHAPTER 4 Reinforcement in addiction
1 INTRODUCTION
Drug addiction is a chronic disease that is often characterized by escalation of drug
intake over time and a pathological and compulsive drug-seeking behavior. Emerg-
ing conceptualizations of drug addiction (or substance use disorder; DSM-5, 2013)
have included a constantly evolving set of defining characteristics (Wise and Koob,
2014). However, the behavioral principle of reinforcement has remained as a central
feature of multiple diagnostic criteria. As such, a fundamental understanding of
reinforcement principles and protocols is essential to model both the psychological
and neurobiological processes separating initial drug use from the eventual develop-
ment of addiction in vulnerable individuals. An ongoing marriage of behavioral and
molecular techniques has driven a steady evolution of the “black box” working
model of human behavior by early psychologists toward the revelation of neurophys-
iological mechanisms linking stimulus processing to action. While drugs of abuse
represent powerful pharmacological agents that produce significant neuroadapta-
tions in the short-term, further clarification of the neuroadaptations that functionally
drive specific elements (e.g., positive vs. negative reinforcement) within the addic-
tion framework is crucial (Kalivas, 2005). Additionally, since addiction can be de-
scribed as an evolving disease whereby recreational drug sampling can quickly
transition to dependence, determining the precise brain circuitry changes associated
with each stage would prove beneficial for the development of new and more effec-
tive therapeutic strategies. A central question is whether reinforcement processes and
underlying neurobiological changes caused by early drug use are simply potentiated
in the addicted state, or whether there is a separate recruitment and potentiation of
additional reinforcement elements and circuitry that is indispensable for the addic-
tion process.
2 POSITIVE AND NEGATIVE REINFORCEMENT

The process of reinforcement is most commonly associated with positive reinforce-
ment, whereby the presence of a motivational stimulus augments or strengthens a
particular behavioral response. Although the antecedent stimulus can be generally
described as subjectively rewarding or hedonically positive, this is not a necessary
requirement for a stimulus to reinforce a response. Likewise, stimuli that are subjec-
tively rewarding are not automatically reinforcing. Consequently, it is important to
distinguish reward from reinforcement as psychological constructs and to investigate
their neurobiological mechanisms separately. Stimuli that do lead to response
strengthening (i.e., reinforcers) may produce either an increase in frequency or du-
ration of responding or a decrease in latency to respond, and an emphasis on mea-
suring such objective criteria is crucial to the study of reinforcement as originally
conceptualized by Skinner (1938). Neuroanatomical and neurochemical substrates
underlying the positive reinforcing effects of abused drugs have been elucidated over
the past few decades, with mesolimbic dopamine and endogenous opioid systems
3 Secondary and conditioned reinforcement 65
that mediate natural reward playing a central role (Corbett and Wise, 1980; Wise and
Bozarth, 1981; Yokel and Wise, 1975). Negative reinforcement is a special condition
associated with a strengthening of behavioral responses that terminate some ongoing
(presumably aversive) stimulus. In this case we can define a negative reinforcer as a
motivational stimulus that strengthens such an “escape” response. Historically, in
relation to drug addiction, this phenomenon has been consistently observed in
humans whereby drugs of abuse are self-administered to quench a motivational need
in the state of withdrawal (Wikler, 1952). It’s worth reiterating that both positive and
negative reinforcement always leads to an increase in organized behavior, and this
relationship stands in contrast to the concept of punishment, whereby behavioral ac-
tion is suppressed or terminated by a stimulus. Importantly, relationships between
stimulus and response are further complicated by timing and contingency.
A stimulus that acts as a negative reinforcer if presented before an action might
be expected to act as a punisher if presented at the same time as (i.e., made contingent
on) the response. As one example, electrical shock may act as an antecedent negative
reinforcer that facilitates a subsequent behavioral action to terminate shock delivery
(if this option is available), whereas any ongoing behavioral action conducted at the
exact time of delivery of the foot shock would be expected to be suppressed.
3 SECONDARY AND CONDITIONED REINFORCEMENT

An important dimension of reinforcement highly relevant to the addiction process
(and particularly relapse) is secondary reinforcement (Stewart, 1992). Secondary re-
inforcers (in many cases also considered conditioned reinforcers) likely drive the ma-
jority of reinforcement processes in humans. In the specific case of drug addition,
cues and contexts that are intimately and repeatedly associated with drug use will
often themselves become reinforcing, leading some to conceptualize addiction as
conditions of disordered reward learning and memory (Hyman et al., 2006;
White, 1996). In this regard conditioned reinforcers may act to precipitate or magnify
craving in withdrawal states, or alternatively to function at a subconscious level to
drive habitual relapse processes (Weiss, 2005; Wikler et al., 1971). A fundamental
piece of Robinson and Berridge’s incentive-sensitization theory of addiction posits
that the incentive value or attractive nature of such secondary reinforcement pro-
cesses, in addition to the primary reinforcers themselves, may persist and even be-
come sensitized over time in league with the development of drug addiction
(Robinson and Berridge, 1993). Indeed, this phenomenon may hold true for both pos-
itive and negative reinforcers (Goldberg and Schuster, 1970; Schulteis and Koob,
1996), and is likely associated with strengthened activity within specific subcortical
circuitry including the amygdala, ventral striatum, prefrontal cortex, and insular cor-
tex (Everitt et al., 1999; Paulus and Stewart, 2014; Peters et al., 2013; White and
Milner, 1992). Subjective craving precipitated by reexposure to (secondary) reinfor-
cing cues and contexts do not diminish but are in fact magnified over the course of
abstinence in human drug addicts (Gawin and Kleber, 1986), possibly in concert with
the discounting of more noble and socially acceptable pursuits and secondary rein-
forcers such as those associated with family and career development. Such discount-
ing is reflected by multiple DSM-5 substance use disorder criteria (e.g., “important
social, occupational, or recreational activities are given up or reduced because of
substance use”) and has been described as a narrowing of behavioral repertoire. This
further underscores the need for preclinical development and testing of novel ther-
apeutics targeting secondary reinforcement mechanisms associated with drug
addiction.
4 MEASURING REINFORCEMENT IN ANIMAL MODELS

The foundations of behavioral analysis as a quantitative science began during Skin-
ner’s time as a graduate student at Harvard University where he originated the op-
erant conditioning chamber in the early 1930s to study response rate as a dependent
variable. Since then, operant self-administration protocols that mimic multiple ele-
ments of the addiction process and timeline (including drug discrimination, intake
escalation, and reinstatement of drug seeking) have been developed. In 1954, James
Olds and Peter Milner at McGill University also found that rats would readily press a
lever to obtain very small amounts of electric current directly into the brain (Olds and
Milner, 1954). Stimulation of specific brain areas (most notably the lateral hypothal-
amus and medial forebrain bundle) supports response rates of thousands of presses
per hour. The reinforcing properties of electrical stimulation (termed intracranial
self-stimulation, ICSS) outweigh virtually all “natural” rewards such as food, water,
and sex, while fluctuations in ICSS thresholds are now believed to reflect temporary
or persistent adjustments in hedonic or reward set point. For example, reinforcing
stimuli are entirely capable of substituting for electrical current in this procedure,
such that ICSS thresholds are lowered following acute administration of various
drugs of abuse ranging from cocaine to heroin (Simon et al., 1979). In addition, acute
abstinence from drugs of abuse, particularly following a history of excessive drug
exposure, reveals elevations in ICSS thresholds thought to represent hedonic deficits
associated with a motivational withdrawal state ( Jang et al., 2013; Kenny et al.,
2006; Schulteis et al., 1995).
Another valuable extension of self-administration models of reinforcement is the
runway model of drug self-administration (Ettenberg, 2009). This procedure com-
bines the traditional operant lever pressing behavior with place conditioning, and
is capable of independently accessing positive reinforcement from antecedent moti-
vation. Ettenberg and colleagues have further used this technique to distinguish the
naturally composite “approach” versus “avoidance” conflict associated with cocaine
as a reinforcing stimulus. Interestingly, animals with a more extensive history of co-
caine self-administration exhibit heightened approach behavior and attenuated
avoidance of cocaine reward (Ben-Shahar et al., 2008).
Animal models of protracted and excessive exposure to drugs and alcohol that
display high construct and predictive validity for the human condition have been
5 Drugs of abuse and emergent withdrawal symptoms as reinforcers 67
developed and are being intensively investigated. These models primarily employ
extended access to intravenous drug self-administration (Ahmed and Koob, 1998)
or chronic, intermittent exposure to dependence-inducing alcohol vapors (Gilpin
et al., 2008; Vendruscolo and Roberts, 2014). Such procedures have demonstrated
significant associations between excessive drug taking, somatic and motivational in-
dices of withdrawal, and persistent drug seeking (e.g., Ahmed et al., 2000), all critical
DSM-5 criteria for substance dependence. The powerful ability of contextual cues to
elicit drug-seeking (or relapse-like) behavior can be readily modeled in animals by a
simple reexposure to the specific environment where drugs or alcohol were self-
administered on previous occasions (Stewart et al., 1984). In this design, and
consistent with the reports of human craving described above, drug seeking in
animals increases time-dependently as the abstinence period progresses (Grimm
et al., 2001; Tran-Nguyen et al., 1998) a phenomenon that likely prolongs and po-
tentiates relapse propensity. Intermittent schedules of repeated abstinence between
drinking sessions also significantly increases alcohol self-administration in rodents
(Simms et al., 2008; Spanagel et al., 1996). In composite, behavioral methodologies
to study reinforcement and addiction in animals arguably represents the most valid
preclinical model of any psychiatric disorder available to neuroscientists (Edwards
and Koob, 2012). Data derived from these models have underscored the notion that
both drug exposure and withdrawal represent dynamic states characterized by pro-
found neuroadaptations that can exacerbate the progression of addiction but can also
be targeted for therapeutic intervention.
5 DRUGS OF ABUSE AND EMERGENT WITHDRAWAL

SYMPTOMS AS REINFORCERS
Research over the past several decades has successfully uncovered the neuroanatom-
ical sites and signaling processes in the brain where various drugs of abuse act to
facilitate their positive reinforcing effects. An abundance of work has implicated as-
cending monoamine signaling, with a particular emphasis on dopamine neurotrans-
mission, although many nondopamine systems also contribute directly or indirectly
to primary reward and reinforcement. Most notably, mesolimbic dopamine system
activation attributes incentive salience to environmental stimuli and facilitates
goal-directed behavior (Everitt et al., 2008; Robinson and Berridge, 1993; Self
and Nestler, 1995) with important contributions from the ventral tegmental area, nu-
cleus accumbens, and amygdala. Psychostimulant drugs (cocaine, amphetamines)
lead to a particularly strong activation of mesolimbic dopamine circuitry, while
dopamine-independent processes and neural substrates are additionally implicated
in opioid and alcohol reinforcement (Shippenberg and Koob, 2002). However, the
neurochemical mechanisms underlying the reinforcing effects of acute and/or lim-
ited drug and alcohol exposure contrast with the additional motivational circuitry
recruited following escalated drug use that most significantly manifests during with-
drawal to promote negative reinforcement (Edwards and Koob, 2013; Fig. 1).
Recreational, limited intake Uncontrolled, excessive intake

Positive reinforcement Negative reinforcement
Mild Severe
Substance use disorder Substance use disorder
FIGURE 1
Reinforcement principles impact virtually all behavioral and neurobiological processes along
the addiction timeline, from initial use to escalation of intake and relapse behavior. However,
the transition from mild to severe substance use disorder is hypothesized to result from a
recruitment and potentiation of negative reinforcement mechanisms in particular.
Negative reinforcers in alcohol dependence

Dependence symptomatology in an animal model of alcoholism
Increased tremor Increased anxiety-like behavior Increased ICSS

Abnormal gait Increased depression-like behavior (Brain reward)
Enhanced startle Increased pain-like behavior thresholds
Somatic symtoms Motivational symptoms

of dependence of dependence
Macey et al. (1996) Valdez et al. (2003) Schulteis et al. (1995)

Roberts et al. (1996) Walker et al. (2010)
Roberts et al. (2000) Edwards et al. (2012)
Gilpin et al. (2008)
FIGURE 2
Somatic and motivational withdrawal symptoms that manifest during alcohol dependence
can represent potent negative reinforcers that promote excessive alcohol drinking.
Indeed, a universal response to both acute withdrawal and attempted protracted

abstinence from virtually all drugs of abuse in humans is the display of negative
affective symptomatology, and numerous animal models have reliably discovered
similar responses during drug and alcohol withdrawal, including increases in
anxiety-, depression-, and hyperalgesia-like behaviors (Edwards and Koob, 2012;
Edwards et al., 2012; Fig. 2).
6 Neuroadaptational intersections 69
6 NEUROADAPTATIONAL INTERSECTIONS OF
REINFORCEMENT PROCESSES IN ADDICTION
The interplay of positive and negative reinforcement endemic to chronic drug expo-
sure and withdrawal has led to the development of an allostatic load model of brain
reinforcement systems to explain the more persistent changes in motivation associ-
ated with the transition to addiction (Koob and Le Moal, 2001). Here, addiction is
considered to result from chronic, intermittent cycles of signaling changes in brain
reward and antireward (or stress) circuitry that ultimately results in the potentiation
of negative emotional states (chronic irritability, somatic and emotional pain, dys-
phoria, and anhedonia; Egli et al., 2012) that serve as profound negative reinforcers.
This imbalance comes as a result of failed homeostatic mechanisms that normally act
to buffer reward and stress function. As such, this theory posits that the magnification
of negative reinforcement processes takes a predominating position over positive re-
inforcement in driving the compulsive seeking and use of drugs. At the neuroanatom-
ical level, the dysregulation of reinforcement systems is hypothesized to be regulated
by two distinct processes, contrasted as “within-system” neuroadaptations versus
“between-system” neuroadaptations (Koob and Le Moal, 2008).
Within-system neuroadaptations often act as opponent processes to a reinforcing
stimulus such as ingestion of a drug. For example, the primary signaling cascade
linked to the drug of abuse might itself adapt to limit the drug’s effects, while per-
sistence of such counterbalancing effects after termination of drug use would pro-
duce a significant somatic and/or motivational withdrawal response. Such a
within-system opponent neuroadaptation within a given motivational brain region
or circuit would therefore result in decreased reward neurotransmitter function over
time. For example, excessive drug use (in contrast to limited drug exposure) leads to
acute withdrawal deficits in dopamine levels and diminished reward function in re-
gions such as the ventral striatum that mediate the initial positive reinforcing effects
of abused drugs (Melis et al., 2005; Weiss et al., 1992). In a between-system neuroa-
daptation, brain regions or systems other than those involved in the initial positive
reinforcing effects of drugs are recruited (and often dysregulated) following chronic
activation. In this case, another distinct neural substrate is activated and exerts op-
posing actions to limit primary reward function. For example, the transition to esca-
lated drug and alcohol use in animal models is associated with the recruitment and
potentiation of numerous and diverse central brain stress systems that may magnify
negative reinforcement processes (Koob et al., 2014; Muschamp and Carlezon,
2013), particularly in combination with the reward deficits described above.
Indeed, a pathological interaction of brain stress and reward systems may repre-
sent a neurophysiological point of intersection between positive and negative rein-
forcement circuitry acting together to promote or maintain drug addiction. While
compromised mesolimbic dopamine levels are associated with anhedonia during
drug withdrawal, this condition may also set the stage for enhanced sensitivity to
reinforcing stimuli that elevate dopamine levels within this circuitry, including stress
(Kalivas and Stewart, 1991; Lammel et al., 2014; Sorg and Kalivas, 1991). One key
mediator of central stress signaling, corticotropin-releasing factor (CRF), also di-
rectly activates dopamine terminals in the nucleus accumbens (Pan et al., 1995),
while drug-induced dopamine release in this area is reduced by CRF receptor block-
ade (Lodge and Grace, 2005). Conversely, mesolimbic dopamine promotes CRF
release (Kash et al., 2008) and CRF-driven behaviors within extended amygdala
areas (Meloni et al., 2006). Moreover, animal models of stress-induced relapse have
identified a circuitry link between the central amygdala and ventral tegmental area
(VTA) that is key to this phenomenon (McFarland et al., 2004). Adding to its sig-
naling properties to regulate amygdala function, CRF also drives VTA activity to
promote stress-primed reinstatement in cocaine-experienced animals (Wang et al.,
2005). Similar interactions between glucocorticoid and dopamine signaling exist
within reinforcement circuitry (Piazza et al., 1996), and corticosterone itself has been
demonstrated to be reinforcing (Piazza et al., 1993). Synergistic relationships be-
tween stress and dopamine systems may make individuals more sensitive to the rein-
forcing effects of drugs as well as expend more effort to obtain the drug of choice
(Ambroggi et al., 2009).

According with the hypothesized transition from positive to negative reinforcement
processes driving excessive drug use (Fig. 1), attenuation of brain stress system over-
activation in individuals suffering from addiction may represent a valid therapeutic
strategy to reduce the impact of aberrant reinforcement on behavior. For example,
systemic and intracerebral administration of CRF receptor antagonists significantly
reduces drug withdrawal-induced behaviors, including conditioned behaviors and
withdrawal symptoms manifest during protracted abstinence (e.g., Heinrichs
et al., 1995; Overstreet et al., 2004; Stinus et al., 2005; Valdez et al., 2003). These
data strongly suggest that blockade of CRF signaling would prevent the ability of
negative affective conditions in withdrawal to serve as negative reinforcers pro-
moting relapse and reescalation of drug intake. At the preclinical level, CRF
receptor antagonists are therapeutically effective in animal models of excessive drug
use, where they block increased drug intake associated with extended access to
intravenous self-administration of cocaine, heroin, and nicotine (George et al.,
2007; Greenwell et al., 2009; Park et al., 2015; Specio et al., 2008). CRF receptor
antagonists also reduce excessive drinking in alcohol-dependent rats (Funk et al.,
2007), while further evidence at the clinical level suggests that antagonists with lon-
ger receptor residence rates might exhibit greater efficacy in reducing drinking
(Kwako et al., 2015). Importantly, CRF antagonism does not appear to alter drug
and alcohol intake in nondependent animals or the intake of natural rewards such
as sucrose or water. As such, these results provide substantial evidence for a specific
role of CRF receptors in the escalation of drug intake associated with negative rein-
forcement. This selectivity would suggest a robust and specific efficacy of this drug
Acknowledgments 71
class to treat addictive disorders, with a critical feature lacking in existing medica-
tions such as naltrexone that suffers from substantial compliance issues (Swift et al.,
2011) due to its primary actions to reduce positive reinforcement mechanisms via
opioid receptor blockade.
Recent data have implicated additional central stress-regulated neuropeptides in
promoting escalation of drug intake and addiction-related symptomatology, such as
the endogenous dynorphin/kappa-opioid receptor system (Butelman et al., 2012). In
contrast to other endogeonous opioids, dynorphin likely plays a central role in neg-
ative reinforcement, as kappa-opioid receptor stimulation produces aversion and an-
hedonia in animal models as well as negative affect in humans (Mucha and Herz,
1985; Pfeiffer et al., 1986; Todtenkopf et al., 2004). Dynorphin inhibits dopamine
release and function, both at the origins and within the terminals of the mesolimbic
dopamine system, representing a within-system neuroadaptation that underlies the
aversive properties of dynorphin (Margolis et al., 2003; Spanagel et al., 1990).
Dynorphin signaling is potentiated by various drugs of abuse (e.g., Lindholm
et al., 2000; Spangler et al., 1993), and in turn, blockade of kappa-opioid receptors
by the antagonist norbinaltorphimine reduces drug and alcohol intake escalation se-
lectively in dependent (but not nondependent) animals (Walker et al., 2012; Wee and
Koob, 2010).
Finally, given its ability to attenuate the efficacy of conditioned reinforcers, the
employment of extinction therapy may represent a useful behavioral strategy to com-
bat relapse to drug and alcohol use in abstinent individuals. Extinction is the process
by which previously conditioned cues and/or contexts gradually lose their motiva-
tional impact following repeated presentation in the absence of the reinforcing stim-
ulus. Unfortunately, a metaanalysis of nine previous extinction therapy trials for drug
addiction failed to uncover a substantial or consistent benefit (Conklin and Tiffany,
2002), although the authors suggested that future trials should strongly consider bas-
ing their methodologies on what has been recently learned from preclinical models of
reinforcement learning. Additional design or treatment variables might incorporate
elements associated with known neuroadaptations resulting from extinction training
that are entirely distinct from the withdrawal process itself (Self et al., 2004). For
example, combinations of extinction therapy and traditional pharmaceutical ap-
proaches targeting endogenous opioid signaling (O’Brien et al., 1984) or glutamate
receptor systems (Myers et al., 2011) would appear to be one promising avenue for
maximizing treatment efficacy. Ultimately, future medical interventions for addic-
tion will need to factor in the inextricable link between the addiction process
and maladaptive changes in underlying positive and negative reinforcement
mechanisms.
ACKNOWLEDGMENTS
Preparation of this work was generously supported by the LSU Health Sciences Center School
of Medicine and the National Institute on Alcohol Abuse and Alcoholism (AA020839, S.E.).
REFERENCES
Ahmed, S.H., Koob, G.F., 1998. Transition from moderate to excessive drug intake: change in
hedonic set point. Science 282, 298–300.
Ahmed, S.H., Walker, J.R., Koob, G.F., 2000. Persistent increase in the motivation to take
heroin in rats with a history of drug escalation. Neuropsychopharmacology 22, 413–421.
Ambroggi, F., Turiault, M., Milet, A., Deroche-Gamonet, V., Parnaudeau, S., Balado, E.,
Barik, J., Van Der Veen, R., Maroteaux, G., Lemberger, T., Schutz, G., Lazar, M.,
Marinelli, M., Piazza, P.V., Tronche, F., 2009. Stress and addiction: glucocorticoid recep-
tor in dopaminoceptive neurons facilitates cocaine seeking. Nat. Neurosci. 12, 247–249.
Ben-Shahar, O., Posthumus, E.J., Waldroup, S.A., Ettenberg, A., 2008. Heightened drug-
seeking motivation following extended daily access to self-administered cocaine. Prog.
Neuropsychopharmacol. Biol. Psychiatry 32, 863–869.
Butelman, E.R., Yuferov, V., Kreek, M.J., 2012. kappa-opioid receptor/dynorphin system:
genetic and pharmacotherapeutic implications for addiction. Trends Neurosci. 35, 587–596.
Conklin, C.A., Tiffany, S.T., 2002. Applying extinction research and theory to cue-exposure
addiction treatments. Addiction 97, 155–167.
Corbett, D., Wise, R.A., 1980. Intracranial self-stimulation in relation to the ascending dopa-
minergic systems of the midbrain: a moveable electrode mapping study. Brain Res.
185, 1–15.
DSM-5, 2013. American Psychiatric Association: Diagnostic and Statistical Manual of Mental
Disorders, fifth ed. American Psychiatric Association, Arlington, VA.
Edwards, S., Koob, G.F., 2012. Experimental psychiatric illness and drug abuse models: from
human to animal, an overview. Methods Mol. Biol. 829, 31–48.
Edwards, S., Koob, G.F., 2013. Escalation of drug self-administration as a hallmark of persis-
tent addiction liability. Behav. Pharmacol. 24, 356–362.
Edwards, S., Vendruscolo, L.F., Schlosburg, J.E., Misra, K.K., Wee, S., Park, P.E.,
Schulteis, G., Koob, G.F., 2012. Development of mechanical hypersensitivity in rats dur-
ing heroin and ethanol dependence: alleviation by CRF(1) receptor antagonism.
Neuropharmacology 62, 1142–1151.
Egli, M., Koob, G.F., Edwards, S., 2012. Alcohol dependence as a chronic pain disorder.
Neurosci. Biobehav. Rev. 36, 2179–2192.
Ettenberg, A., 2009. The runway model of drug self-administration. Pharmacol. Biochem.
Behav. 91, 271–277.
Everitt, B.J., Parkinson, J.A., Olmstead, M.C., Arroyo, M., Robledo, P., Robbins, T.W., 1999.
Associative processes in addiction and reward. The role of amygdala-ventral striatal sub-
systems. Ann. N. Y. Acad. Sci. 877, 412–438.
Everitt, B.J., Belin, D., Economidou, D., Pelloux, Y., Dalley, J.W., Robbins, T.W., 2008.
Review. Neural mechanisms underlying the vulnerability to develop compulsive drug-
seeking habits and addiction. Philos. Trans. R. Soc. Lond. B Biol. Sci. 363, 3125–3135.
Funk, C.K., Zorrilla, E.P., Lee, M.J., Rice, K.C., Koob, G.F., 2007. Corticotropin-releasing
factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent
rats. Biol. Psychiatry 61, 78–86.
Gawin, F.H., Kleber, H.D., 1986. Abstinence symptomatology and psychiatric diagnosis in
cocaine abusers. Clinical observations. Arch. Gen. Psychiatry 43, 107–113.
George, O., Ghozland, S., Azar, M.R., Cottone, P., Zorrilla, E.P., Parsons, L.H.,
O’Dell, L.E., Richardson, H.N., Koob, G.F., 2007. CRF-CRF1 system activation mediates
References 73
withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats.

Proc. Natl. Acad. Sci. U. S. A. 104, 17198–17203.
Gilpin, N.W., Richardson, H.N., Cole, M., Koob, G.F., 2008. Vapor inhalation of alcohol in
rats. Curr. Protocol. Neurosci. Chapter 9, Unit 9 29.
Goldberg, S.R., Schuster, C.R., 1970. Conditioned nalorphine-induced abstinence changes:
persistence in post morphine-dependent monkeys. J. Exp. Anal. Behav. 14, 33–46.
Greenwell, T.N., Funk, C.K., Cottone, P., Richardson, H.N., Chen, S.A., Rice, K.C.,
Zorrilla, E.P., Koob, G.F., 2009. Corticotropin-releasing factor-1 receptor antagonists
decrease heroin self-administration in long- but not short-access rats. Addict. Biol.
14, 130–143.
Grimm, J.W., Hope, B.T., Wise, R.A., Shaham, Y., 2001. Neuroadaptation. Incubation of co-
caine craving after withdrawal. Nature 412, 141–142.
Heinrichs, S.C., Menzaghi, F., Schulteis, G., Koob, G.F., Stinus, L., 1995. Suppression of
corticotropin-releasing factor in the amygdala attenuates aversive consequences of mor-
phine withdrawal. Behav. Pharmacol. 6, 74–80.
Jang, C.G., Whitfield, T., Schulteis, G., Koob, G.F., Wee, S., 2013. A dysphoric-like state dur-
ing early withdrawal from extended access to methamphetamine self-administration in
rats. Psychopharmacology (Berl.) 225, 753–763.
Kalivas, P.W., 2005. How do we determine which drug-induced neuroplastic changes are
important? Nat. Neurosci. 8, 1440–1441.
Kalivas, P.W., Stewart, J., 1991. Dopamine transmission in the initiation and expression of
drug- and stress-induced sensitization of motor activity. Brain Res. Brain Res. Rev.
16, 223–244.
Kash, T.L., Nobis, W.P., Matthews, R.T., Winder, D.G., 2008. Dopamine enhances fast ex-
citatory synaptic transmission in the extended amygdala by a CRF-R1-dependent process.
J. Neurosci. 28, 13856–13865.
Kenny, P.J., Chen, S.A., Kitamura, O., Markou, A., Koob, G.F., 2006. Conditioned withdrawal
drives heroin consumption and decreases reward sensitivity. J. Neurosci. 26, 5894–5900.
Koob, G.F., Le Moal, M., 2001. Drug addiction, dysregulation of reward, and allostasis.
Koob, G.F., Le Moal, M., 2008. Addiction and the brain antireward system. Annu. Rev. Psy-
chol. 59, 29–53.
Koob, G.F., Buck, C.L., Cohen, A., Edwards, S., Park, P.E., Schlosburg, J.E., Schmeichel, B.,
Vendruscolo, L.F., Wade, C.L., Whitfield Jr., T.W., George, O., 2014. Addiction as a
stress surfeit disorder. Neuropharmacology 76 (Pt B), 370–382.
Kwako, L.E., Spagnolo, P.A., Schwandt, M.L., Thorsell, A., George, D.T., Momenan, R.,
Rio, D.E., Huestis, M., Anizan, S., Concheiro, M., Sinha, R., Heilig, M., 2015. The cor-
ticotropin releasing hormone-1 (CRH1) receptor antagonist pexacerfont in alcohol depen-
dence: a randomized controlled experimental medicine study. Neuropsychopharmacology
40, 1053–1063.
Lammel, S., Lim, B.K., Malenka, R.C., 2014. Reward and aversion in a heterogeneous mid-
brain dopamine system. Neuropharmacology 76 (Pt B), 351–359.
Lindholm, S., Ploj, K., Franck, J., Nylander, I., 2000. Repeated ethanol administration induces
short- and long-term changes in enkephalin and dynorphin tissue concentrations in rat
brain. Alcohol 22, 165–171.
Lodge, D.J., Grace, A.A., 2005. Acute and chronic corticotropin-releasing factor 1 receptor
blockade inhibits cocaine-induced dopamine release: correlation with dopamine neuron
activity. J. Pharmacol. Exp. Ther. 314, 201–206.
Macey, D.J., Schulteis, G., Heinrichs, S.C., Koob, G.F., 1996. Time-dependent quantifiable
withdrawal from ethanol in the rat: effect of method of dependence induction. Alcohol
13, 163–170.
Margolis, E.B., Hjelmstad, G.O., Bonci, A., Fields, H.L., 2003. Kappa-opioid agonists directly
inhibit midbrain dopaminergic neurons. J. Neurosci. 23, 9981–9986.
McFarland, K., Davidge, S.B., Lapish, C.C., Kalivas, P.W., 2004. Limbic and motor circuitry
underlying footshock-induced reinstatement of cocaine-seeking behavior. J. Neurosci.
24, 1551–1560.
Melis, M., Spiga, S., Diana, M., 2005. The dopamine hypothesis of drug addiction: hypodo-
paminergic state. Int. Rev. Neurobiol. 63, 101–154.
Meloni, E.G., Gerety, L.P., Knoll, A.T., Cohen, B.M., Carlezon Jr., W.A., 2006. Behavioral
and anatomical interactions between dopamine and corticotropin-releasing factor in the
rat. J. Neurosci. 26, 3855–3863.
Mucha, R.F., Herz, A., 1985. Motivational properties of kappa and mu opioid receptor agonists
studied with place and taste preference conditioning. Psychopharmacology (Berl.)
86, 274–280.
Muschamp, J.W., Carlezon Jr., W.A., 2013. Roles of nucleus accumbens CREB and dynorphin
in dysregulation of motivation. Cold Spring Harbor Perspect. Med. 3, a012005.
Myers, K.M., Carlezon Jr., W.A., DAVIS, M., 2011. Glutamate receptors in extinction and
extinction-based therapies for psychiatric illness. Neuropsychopharmacology
36, 274–293.
O’Brien, C.P., Childress, A.R., McLellan, A.T., Ternes, J., Ehrman, R.N., 1984. Use of nal-
trexone to extinguish opioid-conditioned responses. J. Clin. Psychiatry 45, 53–56.
Olds, J., Milner, P., 1954. Positive reinforcement produced by electrical stimulation of septal
area and other regions of rat brain. J. Comp. Physiol. Psychol. 47, 419–427.
Overstreet, D.H., Knapp, D.J., Breese, G.R., 2004. Modulation of multiple ethanol
withdrawal-induced anxiety-like behavior by CRF and CRF1 receptors. Pharmacol. Bio-
chem. Behav. 77, 405–413.
Pan, J.T., Lookingland, K.J., Moore, K.E., 1995. Differential effects of corticotropin-releasing
hormone on central dopaminergic and noradrenergic neurons. J. Biomed. Sci. 2, 50–56.
Park, P.E., Schlosburg, J.E., Vendruscolo, L.F., Schulteis, G., Edwards, S., Koob, G.F., 2015.
Chronic CRF1 receptor blockade reduces heroin intake escalation and dependence-
induced hyperalgesia. Addict. Biol. 20, 275–284.
Paulus, M.P., Stewart, J.L., 2014. Interoception and drug addiction. Neuropharmacology
76 (Pt B), 342–350.
Peters, G.J., David, C.N., Marcus, M.D., Smith, D.M., 2013. The medial prefrontal cortex is
critical for memory retrieval and resolving interference. Learn. Mem. 20, 201–209.
Pfeiffer, A., Brantl, V., Herz, A., Emrich, H.M., 1986. Psychotomimesis mediated by kappa
opiate receptors. Science 233, 774–776.
Piazza, P.V., Deroche, V., Deminiere, J.M., Maccari, S., Le Moal, M., Simon, H., 1993.
Corticosterone in the range of stress-induced levels possesses reinforcing properties:
implications for sensation-seeking behaviors. Proc. Natl. Acad. Sci. U. S. A.
90, 11738–11742.
Piazza, P.V., Rouge-Pont, F., Deroche, V., Maccari, S., Simon, H., Le Moal, M., 1996. Glu-
cocorticoids have state-dependent stimulant effects on the mesencephalic dopaminergic
transmission. Proc. Natl. Acad. Sci. U. S. A. 93, 8716–8720.
References 75
Roberts, A.J., Cole, M., Koob, G.F., 1996. Intra-amygdala muscimol decreases operant eth-
anol self-administration in dependent rats. Alcohol. Clin. Exp. Res. 20, 1289–1298.
Roberts, A.J., Heyser, C.J., Cole, M., Griffin, P., Koob, G.F., 2000. Excessive ethanol drinking
following a history of dependence: animal model of allostasis. Neuropsychopharmacology
22, 581–594.
Robinson, T.E., Berridge, K.C., 1993. The neural basis of drug craving: an incentive-
sensitization theory of addiction. Brain Res. Brain Res. Rev. 18, 247–291.
Schulteis, G., Koob, G.F., 1996. Reinforcement processes in opiate addiction: a homeostatic
model. Neurochem. Res. 21, 1437–1454.
Schulteis, G., Markou, A., Cole, M., Koob, G.F., 1995. Decreased brain reward produced by
ethanol withdrawal. Proc. Natl. Acad. Sci. U. S. A. 92, 5880–5884.
Self, D.W., Nestler, E.J., 1995. Molecular mechanisms of drug reinforcement and addiction.
Annu. Rev. Neurosci. 18, 463–495.
Self, D.W., Choi, K.H., Simmons, D., Walker, J.R., Smagula, C.S., 2004. Extinction training
regulates neuroadaptive responses to withdrawal from chronic cocaine self-
administration. Learn. Mem. 11, 648–657.
Shippenberg, T.S., Koob, G.F., 2002. Recent advances in animal models of drug addiction and
alcoholism. In: Davis, K.L., Charney, D., Coyle, J.T., Nemeroff, C. (Eds.), Neuropsycho-
pharmacology: The Fifth Generation of Progress. Lippincott Williams and Wilkins,
Philadelphia, PA, pp. 1381–1397.
Simms, J.A., Steensland, P., Medina, B., Abernathy, K.E., Chandler, L.J., Wise, R., Bartlett, S.E.,
2008. Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans
and Wistar rats. Alcohol. Clin. Exp. Res. 32, 1816–1823.
Simon, H., Stinus, L., Tassin, J.P., Lavielle, S., Blanc, G., Thierry, A.M., Glowinski, J., Le
Moal, M., 1979. Is the dopaminergic mesocorticolimbic system necessary for intracranial
self-stimulation? Biochemical and behavioral studies from A10 cell bodies and terminals.
Behav. Neural Biol. 27, 125–145.
Skinner, B.F., 1938. The Behavior of Organisms. Appleton-Century-Crofts, New York, NY.
Sorg, B.A., Kalivas, P.W., 1991. Effects of cocaine and footshock stress on extracellular do-
pamine levels in the ventral striatum. Brain Res. 559, 29–36.
Spanagel, R., Herz, A., Shippenberg, T.S., 1990. The effects of opioid peptides on dopamine
release in the nucleus accumbens: an in vivo microdialysis study. J. Neurochem.
55, 1734–1740.
Spanagel, R., Holter, S.M., Allingham, K., Landgraf, R., Zieglgansberger, W., 1996. Acam-
prosate and alcohol: I. Effects on alcohol intake following alcohol deprivation in the rat.
Eur. J. Pharmacol. 305, 39–44.
Spangler, R., Unterwald, E.M., Kreek, M.J., 1993. ‘Binge’ cocaine administration induces a
sustained increase of prodynorphin mRNA in rat caudate-putamen. Brain Res. Mol. Brain
Res. 19, 323–327.
Specio, S.E., Wee, S., O’Dell, L.E., Boutrel, B., Zorrilla, E.P., Koob, G.F., 2008. CRF(1) re-
ceptor antagonists attenuate escalated cocaine self-administration in rats. Psychopharma-
cology (Berl.) 196, 473–482.
Stewart, J., 1992. Neurobiology of conditioning to drugs of abuse. Ann. N. Y. Acad. Sci.
654, 335–346.
Stewart, J., De Wit, H., Eikelboom, R., 1984. Role of unconditioned and conditioned drug ef-
fects in the self-administration of opiates and stimulants. Psychol. Rev. 91, 251–268.
Stinus, L., Cador, M., Zorrilla, E.P., Koob, G.F., 2005. Buprenorphine and a CRF1 antagonist
block the acquisition of opiate withdrawal-induced conditioned place aversion in rats.
Swift, R., Oslin, D.W., Alexander, M., Forman, R., 2011. Adherence monitoring in naltrexone
pharmacotherapy trials: a systematic review. J. Stud. Alcohol Drugs 72, 1012–1018.
Todtenkopf, M.S., Marcus, J.F., Portoghese, P.S., Carlezon Jr., W.A., 2004. Effects of kappa-
opioid receptor ligands on intracranial self-stimulation in rats. Psychopharmacology
(Berl.) 172, 463–470.
Tran-Nguyen, L.T., Fuchs, R.A., Coffey, G.P., Baker, D.A., O’Dell, L.E., Neisewander, J.L.,
1998. Time-dependent changes in cocaine-seeking behavior and extracellular dopamine
levels in the amygdala during cocaine withdrawal. Neuropsychopharmacology 19, 48–59.
Valdez, G.R., Zorrilla, E.P., Roberts, A.J., Koob, G.F., 2003. Antagonism of corticotropin-
releasing factor attenuates the enhanced responsiveness to stress observed during pro-
tracted ethanol abstinence. Alcohol 29, 55–60.
Vendruscolo, L.F., Roberts, A.J., 2014. Operant alcohol self-administration in dependent rats:
focus on the vapor model. Alcohol 48, 277–286.
Walker, B.M., Drimmer, D.A., Walker, J.L., Liu, T., Mathe, A.A., Ehlers, C.L., 2010. Effects
of prolonged ethanol vapor exposure on forced swim behavior, and neuropeptide Y and
corticotropin-releasing factor levels in rat brains. Alcohol 44, 487–493.
Walker, B.M., Valdez, G.R., McLaughlin, J.P., Bakalkin, G., 2012. Targeting dynorphin/
kappa opioid receptor systems to treat alcohol abuse and dependence. Alcohol
46, 359–370.
Wang, B., Shaham, Y., Zitzman, D., Azari, S., Wise, R.A., You, Z.B., 2005. Cocaine experi-
ence establishes control of midbrain glutamate and dopamine by corticotropin-releasing
factor: a role in stress-induced relapse to drug seeking. J. Neurosci. 25, 5389–5396.
Wee, S., Koob, G.F., 2010. The role of the dynorphin-kappa opioid system in the reinforcing
effects of drugs of abuse. Psychopharmacology (Berl.) 210, 121–135.
Weiss, F., 2005. Neurobiology of craving, conditioned reward and relapse. Curr. Opin. Phar-
macol. 5, 9–19.
Weiss, F., Markou, A., Lorang, M.T., Koob, G.F., 1992. Basal extracellular dopamine levels in
the nucleus accumbens are decreased during cocaine withdrawal after unlimited-access
self-administration. Brain Res. 593, 314–318.
White, N.M., 1996. Addictive drugs as reinforcers: multiple partial actions on memory sys-
tems. Addiction 91, 921–949. discussion 951–965.
White, N.M., Milner, P.M., 1992. The psychobiology of reinforcers. Annu. Rev. Psychol.
43, 443–471.
Wikler, A., 1952. A psychodynamic study of a patient during experimental self-regulated
re-addiction to morphine. Psychiatr. Q. 26, 270–293.
Wikler, A., Pescor, F.T., Miller, D., Norrell, H., 1971. Persistent potency of a secondary (con-
ditioned) reinforcer following withdrawal of morphine from physically dependent rats.
Psychopharmacologia 20, 103–117.
Wise, R.A., Bozarth, M.A., 1981. Brain substrates for reinforcement and drug self-
administration. Prog. Neuropsychopharmacol. 5, 467–474.
Wise, R.A., Koob, G.F., 2014. The development and maintenance of drug addiction.
Yokel, R.A., Wise, R.A., 1975. Increased lever pressing for amphetamine after pimozide in
rats: implications for a dopamine theory of reward. Science 187, 547–549.
CHAPTER
Neuroscience of attentional
processes for addiction
medicine: from brain
mechanisms to practical
5
considerations
Javad Salehi Fadardi*,†,{,1, W. Miles Cox†, Arash Rahmani}
*Ferdowsi University of Mashhad, Mashhad, Iran
†
Bangor University, Bangor, UK
{
Addiction Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran
}
Iranian National Center for Addiction Studies, Tehran University of Medical Sciences,
Tehran, Iran
1
Corresponding author: Tel.: +988138805867; Fax: +988138805867,
Abstract
The present chapter first argues how having a goal for procuring alcohol or other substances
leads to the development of a time-binding, dynamic, and goal oriented motivational state
termed current concern, as the origin of substance-related attentional bias. Next, it discusses
the importance of attentional bias in the development, continuation of, and relapsing to sub-
stance abuse. It further proceeds with a review of selective evidence from cognitive psychol-
ogy that helps account for making decisions about using an addictive substance or refraining
from using it. A discussion on the various brain loci that are involved in attentional bias and
other kinds of cue reactivity is followed by presenting findings from neurocognitive research.
Finally, from an interdisciplinary perspective, the chapter presents new trends and ideas that
can be applied to addiction-related cognitive measurement and training.
Keywords
Motivation, Current concern, Attentional bias, Brain, Attention retraining, Implicit cognition,
Technology

77
78 CHAPTER 5 Neuroscience of attentional processes
1 INTRODUCTION
Attentional bias means that a person selectively attends to a certain category or cer-
tain categories of stimuli in the environment while tending to overlook, ignore, or
disregard other kinds of stimuli. For example, one person might selectively attend
to stimuli related to food (particularly food that is perceived to be particularly deli-
cious). Sexual stimuli might be particularly distracting for another person; fashion-
related stimuli might capture another person’s attention. Of greater relevance for the
present chapter is that certain other people are distracted by addiction-related stimuli.
The latter stimuli might be ones related to alcohol, another substance of abuse, or
some other form of addiction (e.g., gambling) (Fig. 1).
What do these different kinds of attentional bias mean, and how do they arise?
Often—if not always—the attentional bias is motivationally relevant, i.e., it is related
to the person’s goal-directed behavior. Formally, we define motivation as “the inter-
nal states of the organism that lead to the instigation, persistence, energy, and direc-
tion of behavior towards a goal” (Klinger and Cox, 2011, p. 4). How do such states
come about, and how do they give rise to attentional bias?
Motivation starts when a person is aware of incentives that he or she finds attrac-
tive. An incentive is defined as any object or event that could potentially change a
person’s affect in a positive way, either by enhancing positive affect or by reducing
negative affect. In addition to incentive, affect and affective change are, therefore,
key motivational constructs. Affect—which can be either positive or negative—is
the subjective component of an emotional response. Affective change is a change
in affect from its present state; it is the essence of what people are motivated to
achieve. People want to feel better than they currently do, either by increasing their
positive affect (e.g., joy, happiness, or satisfaction) or by decreasing their negative
affect (e.g., fear, boredom, or depression).
Of the many positive incentives that could potentially enhance a person’s positive
affect and the many negative incentives that could reduce the person’s negative af-
fect if they were removed, each person might set a goal of acquiring only a subset of
the positive incentives or a goal of getting rid of only a subset of the negative incen-
tives. In either case, a goal is formed from the moment that the person makes a com-
mitment to either obtain or to get rid of an incentive.
Why are some incentives but not others transformed into goals? Motivational
psychologists often rely on Value X Expectancy Theory (Bundorf et al., 2013;
Cox et al., 2015; Morone and Morone, 2014) to explain this outcome. According
to this theory, two primary variables determine whether an incentive is transformed
into a goal. They are (a) the value that the person attributes to the incentive (how
valuable to the person the affective change that the incentive would produce would
be) and (b) the person’s expected likelihood of actually being able to obtain the in-
centive if he or she puts forth the effort. Because the relationship between value and
expectancy is multiplicative, if either of them is zero (or near zero), a goal to pursue
the incentive will not be formed. For example, a person might imagine that becoming
a millionaire would bring about a very positive affective change, but the person
1 Introduction 79
• Attentional bias (AB) is motivationally relevant.

Motivational basis of • Anticipated affective change is the essence of
attentional bias what motivates people to achieve their goals.
• When a person has a goal, he or she selectively
attends to stimuli in the environment that are
related to the goal.
• AB affects cognitive processes involved in decision

making.
Clinical relevance of • AB has shown promise for screening, diagnosis,
attentional bias and predicting treatment outcomes.
• Differential patterns of brain activation in response
to substance-related and other higher order goal
cues have important clinical implications.
• AB plays an important role in the maintenance of

Therapeutic and relapsing to addictive behaviors.
implications of • Various cognitive methods have been used to
attentional bias reduce AB.
• Pharmacological interventions and brain
stimulation have shown beneficial effects on
substance-related AB.
• Findings from other areas of research might help

improve assessments of and interventions for AB.
Conclusions and future • A person’s biological reactivity related to feelings of
directions
craving can affect the AB.
• Virtual lesion techniques might help to localize brain
areas involved in cue reactivity and AB.
• Impairment in other brain loci and emotional
dysregulation might adversely affect AB
modification.
FIGURE 1
Summary of the main topics that have been discussed in the present chapter.
might not actually try to become a millionaire because the expected chances of being
able to do so are virtually nil.
People, of course, vary widely with regard to the value that they attribute to using
addictive substances and their actual use of them. What are the factors that determine
the value of using these substances? To answer this question, we will use alcohol
consumption as an example; nevertheless, much of the discussion can be generalized
to use of other kinds of addictive substances.
One kind of variable that affects the value of drinking alcohol is each person’s
own biochemical reaction to alcohol (e.g., Dickson et al., 2006). Pharmacologically,
some people react positively to drinking alcohol, and they experience few negative
consequences. Other people experience primarily unpleasant reactions, such as facial
flushing and nausea. Sociocultural and environmental factors also affect the value of
drinking alcohol (e.g., Dantzer et al., 2006). Societies differ widely in how they view
drinking alcohol and the extent to which they condone or prohibit it; thus, people
living in a particular society will be overtly or subtly reinforced for drinking in
the same manner as other people living in that society. Within each society, addi-
tional environmental factors—such as advertising alcohol and taxation on alcohol
and the extent to which drinking alcohol is promoted in a particular situation
(e.g., Hollingworth et al., 2006; Huckle et al., 2008; Paschall et al., 2014)—also
affect the value that people attribute to drinking alcohol.
Other characteristics of individuals themselves (other than each person’s bio-
chemical reactivity to alcohol) might affect the degree to which they value drinking.
Notable among these is each person’s personality characteristics (e.g., see Vrieze
et al., 2014) and the degree to which they are feeling stressed because of frustrations
in other areas of their lives (Demirbas et al., 2012).
As in the case of all goal pursuits, a person will form a goal of drinking alcohol or
using another addictive substance when both (a) the value that the person attributes to
using the substance (the expected desirable affective change) is high and (b) the per-
son’s expected chances of being able to actually achieve the desired change in affect
is high. When the goal is formed, the person is in a distinctive motivational state—
called a current concern (Cox et al., 2015; Klinger and Cox, 2011). This state lasts
from the moment that the commitment to the goal pursuit is first made until either the
goal is reached or the pursuit of the goal is relinquished. During this period, the goal
striving is reflected in the person cognitive processes (e.g., his or her thoughts, mem-
ories, attention, and even dreams). The construct current concern is presumed to re-
fer to latent goal-related brain processes, and recent neuroscientific research has
identified clues about how these processes are represented in the brain (Berkman
and Lieberman, 2009; Klinger and Cox, 2011; Kouneiher et al., 2009). For example,
expected satisfaction from goal attainments are mainly processed in amygdala and
with interactions with orbital prefrontal and anterior cingulate cortex; the interac-
tions among these structures help to determine anticipated goal outcomes, cue reac-
tivity, and response selections (Baxter et al., 2000; Murray, 2007). Later in the
chapter, we discuss how anterior cingulate cortex plays an important role in deter-
mining attentional bias for addiction-related cues. In any case when a person has a
goal of drinking alcohol, the person selectively attends to stimuli in the environment
that are related to procuring and imbibing alcohol. This process facilitates the goal
striving by increasing the person’s motivation to drink and his or her actual consump-
tion of alcohol.
Extensive research has been conducted on alcohol and other substance-related
attentional bias (e.g., Cox et al., 2006) and other kinds of cognitive biases (e.g., au-
tomatic action tendencies; Wiers et al., 2011) related to people’s goal of drinking
alcohol. In the following sections, we (a) briefly review this research, (b) describe
how dual process models help to account for decisions about whether or not to
2 Clinical relevance of attentional bias 81
use an addictive substance, (c) discuss how various brain loci are involved in atten-
tional bias and other kinds of cue reactivity, and (d) suggest how findings from neu-
rocognitive research can be applied to cognitive training and future research.
2 CLINICAL RELEVANCE OF ATTENTIONAL BIAS: IS

ATTENTIONAL BIAS AND ARTIFACT OF IMPAIRED EXECUTIVE
CONTROL?
Substance abuse has adverse effects on the entire body, including the brain. It can
impair the brain’s prefrontal and frontal loci that are mainly responsible for executive
cognitive functions (ECF), including inhibition, task switching, sustained attention,
decision making, and planning (de la Monte and Kril, 2014; Terrett et al., 2014;
Vonmoos et al., 2014). Performance on measures of attentional bias and other im-
plicit cognition tasks requires the involvement of ECFs and working memory. For
example, on an addiction Stroop test (Cox et al., 2006), which measures attentional
bias for substance-related stimuli, the individual needs to inhibit the distracting fea-
ture of a stimulus (e.g., alcohol) and mentally switch to the experimental task
(responding to the color of the stimulus) and keep this task requirement continuously
in mind. As mentioned earlier, alcohol and other drugs of abuse adversely affect
higher order processes; therefore, the question is whether we can attribute longer la-
tencies on measures of attentional bias to the substance-related characteristics of the
stimuli. Or could longer latencies on addiction-related tasks simply result from im-
paired ECFs. Additionally, there are studies suggesting that other characteristics of
abusers, such as their impulsivity or poor inhibitory control, can also affect their per-
formance on attentional bias tasks (Liu et al., 2011).
Fadardi and Cox (2006) found that longer latencies on measures of attentional
bias were not a result only of poorer ECF. They tested alcohol abusers using general
cognitive measures and an alcohol-Stroop test. The results suggested that excessive
drinking sensitized the abusers’ attentional responsiveness to alcohol-related stimuli
to a degree that exceeded the drinkers’ ECF. In other words, the addiction-related
attentional bias was not an artifact of cognitive impairment that either preceded
or followed the alcohol abuse. A clinically valuable method would be able to
(a) screen clinical samples, (b) differentiate among various levels of problem sever-
ity, and (c) predict treatment outcome. In fact, several reviews suggest that implicit
measures of addiction-related cognitive biases have diagnostic and prognostic valid-
ity (Cox et al., 2006; Field and Cox, 2008; Leeman et al., 2014).
In a recent study, a cocaine version of the Stroop test and neuroimaging were used
to differentiate recreational users from abusers. Cocaine-dependent individuals
showed significantly larger attentional bias for cocaine words, but nonusers and rec-
reational users did not show the bias. Moreover, recreational users showed a distinc-
tive pattern of underactivation in prefrontal cortices, including orbitofrontal and
anterior cingulate during task performance compared to both dependent and control
participants (Smith et al., 2014). Janes et al. (2010) used fMRI to assess brain activity
related to attentional bias for smoking-related stimuli on a Stroop test. They reported
that both measures predicted treatment outcome during an 8-week smoking cessation
period.
3 ATTENTION RETRAINING: A MULTIMODAL ACTIVITY

Evidence from cognitive neuroscience suggests that ignoring addiction-related stim-
uli requires increased activation of control networks and reduced processing in emo-
tion and reward regions of the brain. Although during attentional bias drug abusers
typically show increased activity in the regions associated with cognitive control
(i.e., lateral prefrontal and dorsal anterior cingulate), such increases seem to be in-
sufficient to overcome simultaneous increases in processing in the emotion/reward
regions (i.e., amygdala, insula, and striatum) (Hester and Luijten, 2014). In another
study ( Janes et al., 2010), when heavy smokers were exposed to smoking-related
words, increased activation in the brain’s bilateral anterior insula and dorsal anterior
cingulate cortex were observed.
There are similarities in the brain regions that react to drug-related and drug-
unrelated stimuli. For example, Lorenz et al. (2013) reported that gamblers showed
stronger brain responses in medial prefrontal cortex (MPFC) during short presenta-
tions of gambling stimuli (i.e., attentional bias), but stronger brain responses in an-
terior cingulate gyrus and in lingual gyrus during long presentations of gambling
stimuli (i.e., cue reactivity). The authors also reported that in long presentations
of gambling-related stimuli (when participants’ task was to ignore them), stronger
brain responses were observed in right inferior frontal gyrus (associated with inhi-
bition processing), left orbitofrontal cortex, and ventral striatum.
What actually happens when there is increased activity in certain loci of the brain
in response to addiction-related stimuli? According to Franken (2003), a conditioned
drug stimulus produces increase in dopamine in the corticostriatal circuit, particu-
larly in the anterior cingulate gyrus, amygdala, and nucleus accumbens; the increase
serves to draw the person’s attention toward a drug-related stimulus. The process also
results in motor preparation and hyper-attentiveness for drug-related stimuli, which
ultimately promotes craving and perhaps relapse. An implication for treatment
would be to frequently expose abusers to dopamine-releasing stimuli but to prevent
them from taking the substance. This could gradually attenuate the dopamine-
releasing characteristic of the addictive stimuli.
It is interesting to note that such conditioned brain responses in abusive or heavy
drinkers are not limited to the brain’s maladaptive neural responses to addiction-
related stimuli; rather, anomalies can also be observed in the brain’s reactivity to other
kinds of stimuli. In an fMRI study, Ihssen et al. (2011) exposed heavy drinkers to vi-
sual cues that were related to alcohol. Similar to the findings of other studies, parts of
the brain that are involved in emotional processing (i.e., insular cortex) and reward
circuitry (i.e., ventral striatum) showed greater activity in heavy drinkers than light
drinkers. When heavy drinkers were presented with visual stimuli that were related
5 Pharmacological interventions 83
to their higher order life goals (such as those related to family, health, and finances)
they showed weaker responses in frontal areas than the light drinkers. They also
showed reduced activity in the cingulate cortex when exposed to attractive food stim-
uli. These findings suggest that heavy drinkers have difficulty forming socially desir-
able goals as an alternative to drinking alcohol. The combination of overactivation to
cues related to alcohol but underactivation to cues related to alternative, alcohol-
unrelated goals may have important clinical implications. These findings suggest that
interventions that decrease alcohol abusers’ hyperreactivity to alcohol-related stimuli
but increase their sensitivity to alternative goals might be beneficial.
4 ATTENTIONAL BIAS: THERAPEUTIC IMPLICATIONS

Given the potential role of attentional bias in continuation of and relapsing to addic-
tive behaviors, various methods have been used to reduce the bias (Field et al., 2014).
However, there are few double-blind clinical trials that report the effects of atten-
tional bias retraining on treatment outcomes or relapse prevention (Begh et al.,
2013). Nevertheless, among other methods for targeting addictive cognitions, such
as implicit interpretations or approach-avoidance response tendencies, attentional
bias modification has been the focus of much research (see Cox et al., 2014). As
Cox et al. (2014) discussed, practical applications of attentional retraining are being
developed; for example, a mobile phone application has been created to help people
with various types of addictive behaviors to overcome their attentional bias. Wiers
et al. (2015) used a modified version of the Alcohol Attention Control Training Pro-
gram for delivery over the Internet to help alcohol abusers decrease their attentional
bias. Finally, in an ongoing research project funded by the European Commission
called BRAINTRAIN and using fMRI technology (Linden et al., 2015), alcohol-
dependent participants are being trained to downregulate their brain reactions to
alcohol-related pictorial stimuli. In turn, the short- and long-term effects of the train-
ing on participants’ urges to drink alcohol and their alcohol consumption are being
assessed. The general principle used in various types of attentional retraining pro-
grams is to help abusers improve their brain’s inhibitory processes so that they
can more easily disengage their attention from environmental stimuli related to al-
cohol or other substances of abuse. The training programs help trainees to divert their
attention to alternative (usually neutral) stimuli while they try to ignore the emotion-
ally salient stimuli (e.g., the drug-related ones). However, could there be other more
nondirective methods that do not require much effort by the person to desensitize his/
her addiction-related attentional system?
5 PHARMACOLOGICAL INTERVENTIONS
Several studies have investigated the effectiveness of different kinds of medication
for substance abusers (for a review, see Luijten et al., 2013). Some of these studies
have employed fMRI to monitor neuronal activation in response to drug stimuli,
which could provide information about specific brain–behavior modulations.

Machielsen et al. (2014) conducted a randomized controlled trial to compare the ef-
fectiveness of Clozapine with Risperidone in reducing subjective craving, attentional
bias, and brain activation in patients with both schizophrenia and cannabis use dis-
orders (CUDs). Although no differences between CUD and non-CUD patients’ be-
havior were observed, Clozapine-treated CUD participants showed greater
reductions in their subjective craving and in the activation of insula during the com-
pletion of a cannabis-related Stroop test.
There are likely multiple benefits of pharmacological interventions for substance
abuse (e.g., Nalteroxon, nicotine patches). There is evidence, for example, that an
intervention that helps to reduce alcohol or drug use increases in the abuser’s sense
of control (Leeman et al., 2014). Similarly, there is evidence that craving for a sub-
stance of abuse can be reduced by improving a person’s sense of control, whether
through a cognitive-behavioral intervention (e.g., Shamloo and Cox, 2014) or stim-
ulation of the brain’s dorsolateral prefrontal cortex (DLPC) using repetitive transcra-
nial magnetic stimulation (rTMS) (Mishra et al., 2010) and transcranial direct current
stimulation (tDCS) (Naylor et al., 2014).
6 NONINVASIVE BRAIN STIMULATION

There is consensus that stimulation of DLPC is associated with increases in cognitive
control (Leeman et al., 2014) and enhanced processing of emotional stimuli. Brunoni
et al. (2014) conducted a study with depressed participants who completed an emo-
tional Stroop test containing neutral, positive, and negative emotional words while
receiving active or sham tDCS. The results showed that participants receiving active
tDCS were better able to suppress their attentional bias for negative emotional words.
In a recent study, Clarke et al. (2014) used a combination of active or sham left tDCS
and attentional bias modification. They reported that the combination of active
tDCS and attentional bias modification led to greater reduction in attentional bias.
From Jansen et al.’s (2013) review of 17 studies using repetitive rTSM and tDCS
on left or right stimulation of DLPFC, the authors concluded that both methods
yielded a medium effect size for reducing craving for substances of abuse and for
palatable food. Considering the prior established association between craving and
attentional bias (Nikolaou et al., 2013), it would also be expected that noninvasive
brain stimulation (NIBS) would be effective in reducing attentional bias. Indeed, pre-
liminary findings suggest that using NIBS to reduce attentional bias and substance
use is effective. For instance, Meng et al. (2014) found that bilateral cathodal stim-
ulation of frontoparietotemporal areas significantly decreased both attention to
smoking-related cues and cigarette use. Additionally, Hoppner et al. (2011) found
preliminary support for the effectiveness of rTMS in reducing alcohol-related
attentional bias.
7 Conclusions and future directions 85
7 CONCLUSIONS AND FUTURE DIRECTIONS

Evidence suggests that attentional bias plays an important role in sustaining addic-
tive behaviors. However, incorporating new findings from other areas of research
might help to improve assessment of attentional bias and interventions for it.
Field et al. (2014) reviewed the literature on attentional bias and concluded that it
is associated with subjective craving, and that moment-by-moment fluctuations in
attentional bias might precede relapse to substance use. One suggestion for future
research would be to investigate events and feelings that precede subjective craving
and attentional bias for substance-related stimuli. For example, portable devices
might allow substance abusers to measure and record momentary changes in their
attentional bias under various conditions and in various situations. The precision
of the measurement could be improved by recording the person’s biological reactiv-
ity prior to, during, and after feelings of craving. To this end, there would be various
methods to employ, e.g., experience sampling method, ecological momentary assess-
ment, ambulatory assessment, and day reconstruction method (see Trull et al., 2009).
Choi et al. (2015) used neuronavigation-guided rTMS to induce virtual lesions in
selected areas of the brain. With this technique, they reported that posterior temporal
lobe plays an important role in lexical decision making. It would be possible to use
the same technique to induce virtual lesions in the areas of the brain that presumably
play a role in attentional bias. This technique could have important implications for
precisely localizing the brain areas involved in cue reactivity and attentional bias,
and it might help in the development of new clinical interventions to reduce
unwanted attentional bias.
Each person’s attentional bias varies across time, and it might be difficult to gen-
eralize directly from laboratory data (e.g., obtained with fMRI) to applied situations
(e.g., when the person is experiencing craving or is about to relapse). Therefore, in
future research it would be more clinically relevant to assess attentional bias in nat-
ural settings using ecologically valid methods (e.g., experience sampling techniques)
(Field et al., 2014).
Although epidemiological studies have pointed to an increase in methamphet-
amine use in recent decades (UNODC, 2012), the majority of studies of attentional
bias and substance use have focused on alcohol or nicotine; a few studies have
addressed opiates and cocaine use; but methamphetamine use has not been consid-
ered. It would be beneficial in future research to research a wide range of substances
and their clinical implications.
Converging evidence from animal studies (George et al., 2012; Holmes and
Wellman, 2009) suggests that (a) impairment of prefrontal cortex (mPFC), which
is responsible for ECFs, and (b) overactivation of the central nucleus of the amygdala
is associated with excessive drinking and alcohol dependence. Similar findings have
been reported from neurological studies with alcohol abusers (Koob, 2009), indicat-
ing that impairment of the brain’s systems that are responsible for emotional
dysregulation are associated with poorer treatment outcomes in alcohol abuse.
Therefore, attentional bias retraining under laboratory conditions might not benefit
alcohol-dependent people when they are in stressful situations. In other words, those
dependent on alcohol should perhaps receive some type of brain intervention prior to
receiving attentional bias modification.
Given the important role of attentional bias in addictive behaviors and the need
for interventions (both pharmaceutical and cognitive behavioral) to counteract the
bias, understanding the neural basis for successfully reducing the bias remains an
important, but as yet unanswered, question. In future research, methods such as
QEEG, ERP, or fMRI might be employed for brain mapping of cue reactivity to help
identify addictive dispositions at preclinical stages and to clarify the mechanisms
that underlie the development and maintenance of alcohol dependence or other types
of addictive behaviors.
REFERENCES
Baxter, M.G., Parker, A., Lindner, C.C., Izquierdo, A.D., Murray, E.A., 2000. Control of re-
sponse selection by reinforcer value requires interaction of amygdala and orbital prefrontal
cortex. J. Neurosci. 20, 4311–4319.
Begh, R., Munafo, M.R., Shiffman, S., Ferguson, S.G., Nichols, L., Mohammed, M.A.,
Holder, R.L., Sutton, S., Aveyard, P., 2013. Attentional bias retraining in cigarette smokers
attempting smoking cessation (ARTS): study protocol for a double blind randomised con-
trolled trial. BMC Public Health 13, 1176.
Berkman, E.T., Lieberman, M.D., 2009. The neuroscience of goal pursuit: bridging gaps be-
tween theory and data. In: Moskowitz, G., Grant, H. (Eds.), The Psychology of Goals.
Guilford Press, New York, NY, pp. 98–126.
Brunoni, A.R., Zanao, T.A., Vanderhasselt, M.A., Valiengo, L., De Oliveira, J.F., Boggio, P.S.,
Lotufo, P.A., Bensenor, I.M., Fregni, F., 2014. Enhancement of affective processing in-
duced by bifrontal transcranial direct current stimulation in patients with major depression.
Neuromodulation 17, 138–142.
Bundorf, M.K., Mata, R., Schoenbaum, M., Bhattacharya, J., 2013. Are prescription drug in-
surance choices consistent with expected utility theory? Health Psychol. 32, 986–994.
Clarke, P.J., Browning, M., Hammond, G., Notebaert, L., Macleod, C., 2014. The causal role
of the dorsolateral prefrontal cortex in the modification of attentional bias: evidence from
transcranial direct current stimulation. Biol. Psychiatry 76, 946–952.
Cox, W.M., Fadardi, J.S., Pothos, E.M., 2006. The addiction-stroop test: theoretical consid-
erations and procedural recommendations. Psychol. Bull. 132, 443–476.
Cox, W.M., Fadardi, J.S., Intriligator, J.M., Klinger, E., 2014. Attentional bias modification
for addictive behaviors: clinical implications. CNS Spectr. 19 (3), 215–224. http://dx.doi.
org/10.1017/S1092852914000091.
Cox, W.M., Klinger, E., Fadardi, J.S., 2015. Nonconscious motivational influences on cogni-
tive processes in addictive behaviors. In: Heather, N., Segal, G. (Eds.), Addiction and
Choice. Oxford University Press, Oxford, UK. in press.
Choi, Y.H., Park, H.K., Paik, N.J., 2015. Role of the posterior temporal lobe during language
tasks: a virtual lesion study using repetitive transcranial magnetic stimulation. Neuroreport
26 (6), 314–319. http://dx.doi.org/10.1097/WNR.0000000000000339.
References 87
Dantzer, C., Wardle, J., Fuller, R., Pampalone, S.Z., Steptoe, A., 2006. International study of
heavy drinking: attitudes and sociodemographic factors in university students. J. Am. Coll.
Health 55, 83–89.
De La Monte, S.M., Kril, J.J., 2014. Human alcohol-related neuropathology. Acta Neuro-
pathol. 127, 71–90.
Demirbas, H., Ilhan, I.O., Dogan, Y.B., 2012. Ways of problem solving as predictors of relapse
in alcohol dependent male inpatients. Addict. Behav. 37, 131–134.
Dickson, P.A., James, M.R., Heath, A.C., Montgomery, G.W., Martin, N.G., et al., 2006. Ef-
fects of variation at the ALDH2 locus on alcohol metabolism, sensitivity, consumption,
and dependence in Europeans. Alcohol. Clin. Exp. Res. 30, 1093–1100.
Fadardi, J.S., Cox, W.M., 2006. Alcohol attentional bias: drinking salience or cognitive im-
pairment? Psychopharmacology (Berl) 185, 169–178.
Field, M., Cox, W.M., 2008. Attentional bias in addictive behaviors: A review of its develop-
ment, causes, and consequences. Drug Alcohol. Depend. 97 (1–2), 1–20.
Field, M., Marhe, R., Franken, I.H.A., 2014. The clinical relevance of attentional bias in sub-
stance use disorders. CNS Spectr. 19, 225–230.
Franken, I.H., 2003. Drug craving and addiction: integrating psychological and neuropsycho-
pharmacological approaches. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 563–579.
George, O., Sanders, C., Freiling, J., Grigoryan, E., VU, S., Allen, C.D., Crawford, E.,
Mandyam, C.D., Koob, G.F., 2012. Recruitment of medial prefrontal cortex neurons dur-
ing alcohol withdrawal predicts cognitive impairment and excessive alcohol drinking.
Proc. Natl. Acad. Sci. USA 109, 18156–18161.
Hester, R., Luijten, M., 2014. Neural correlates of attentional bias in addiction. CNS Spectr.
19, 231–238.
Hollingworth, W., Ebel, B.E., McCarty, C.A., Garrison, M.M., Christakis, D.A., et al., 2006.
Prevention of deaths from harmful drinking in the United States: the potential effects of tax
increases and advertising bans on young drinkers. J. Stud. Alcohol 67, 300–308.
Holmes, A., Wellman, C.L., 2009. Stress-induced prefrontal reorganization and executive dys-
function in rodents. Neurosci. Biobehav. Rev. 33, 773–783.
Hoppner, J., Broese, T., Wendler, L., Berger, C., Thome, J., 2011. Repetitive transcranial mag-
netic stimulation (rTMS) for treatment of alcohol dependence. World J. Biol. Psychiatry
12 (Suppl. 1), 57–62.
Huckle, T., Huakau, J., Sweetsur, P., Huisman, O., Casswell, S., 2008. Density of alcohol out-
lets and teenage drinking: living in an alcogenic environment is associated with higher
consumption in a metropolitan setting. Addiction 103, 1614–1621.
Ihssen, N., Cox, W.M., Wiggett, A., Fadardi, J.S., Linden, D.E., 2011. Differentiating heavy
from light drinkers by neural responses to visual alcohol cues and other motivational stim-
uli. Cereb. Cortex 21, 1408–1415.
Janes, A.C., et al., 2010. Brain reactivity to smoking cues prior to smoking cessation predicts
ability to maintain tobacco abstinence. Biol. Psychiatry 67, 722–729.
Jansen, J.M., Daams, J.G., Koeter, M.W., Veltman, D.J., Van Den Brink, W., Goudriaan, A.E.,
2013. Effects of non-invasive neurostimulation on craving: a meta-analysis. Neurosci.
Biobehav. Rev. 37, 2472–2480.
Klinger, E., Cox, W.M., 2011. Motivation and the goal theory of current concerns. In: Cox, W.M.,
Klinger, E. (Eds.), Handbook of Motivational Counseling, Second ed. Wiley-Blackwell,
Chichester, UK, pp. 3–47.
Koob, G.F., 2009. Brain stress systems in the amygdala and addiction. Brain Res. 1293, 61–75.
Kouneiher, F., Charron, S., Koechlin, E., 2009. Motivation and cognitive control in the human
prefrontal cortex. Nat. Neurosci. 12, 939–945.
Leeman, R.F., Bogart, D., Fucito, L.M., Boettiger, C.A., 2014. “Killing Two Birds with One
Stone”: alcohol use reduction interventions with potential efficacy in enhancing self-
control. Curr. Addict. Rep. 1, 41–52.
Linden, D.E.J., et al., 2015. BRAINTRAIN. Taking imaging into the therapeutic domain: self-
regulation of brain systems for mental disorders. Ongoing research funded by the
European Commission. Grant agreement no: 602186.
Liu, S., Lane, S.D., Schmitz, J.M., Waters, A.J., Cunningham, K.A., Moeller, F.G., 2011. Re-
lationship between attentional bias to cocaine-related stimuli and impulsivity in cocaine-
dependent subjects. Am. J. Drug Alcohol Abuse 37, 117–122.
Lorenz, R.C., Kruger, J.K., Neumann, B., Schott, B.H., Kaufmann, C., Heinz, A.,
Wustenberg, T., 2013. Cue reactivity and its inhibition in pathological computer game
players. Addict. Biol. 18, 134–146.
Luijten, M., Field, M., Franken, I.H.a., 2013. Pharmacological interventions to modulate at-
tentional bias in addiction. CNS Spectr. 19, 239–246.
Machielsen, M.W., et al., 2014. The effect of clozapine and risperidone on attentional bias in
patients with schizophrenia and a cannabis use disorder: an fMRI study.
J. Psychopharmacol. (Oxford, England) 28, 633–642.
Meng, Z., et al., 2014. Transcranial direct current stimulation of the frontal-parietal-temporal
area attenuates smoking behavior. J. Psychiatr. Res. 54, 19–25.
Mishra, B.R., Nizamie, S.H., Das, B., Praharaj, S.K., 2010. Efficacy of repetitive transcranial
magnetic stimulation in alcohol dependence: a sham-controlled study. Addiction
105, 49–55.
Morone, A., Morone, P., 2014. Estimating individual and group preference functionals using
experimental data. Theor. Decis. 77, 403–422.
Murray, E.A., 2007. The amygdala, reward and emotion. Trends Cogn. Sci. 11, 489–497.
Naylor, J.C., Borckardt, J.J., Marx, C.E., Hamer, R.M., Fredrich, S., Reeves, S.T., George, M.S.,
2014. Cathodal and anodal left prefrontal tDCS and the perception of control over pain. Clin.
J. Pain 30, 693–700.
Nikolaou, K., et al., 2013. Acute alcohol effects on attentional bias are mediated by subcortical
areas associated with arousal and salience attribution. Neuropsychopharmacology
38, 1365–1373.
Paschall, M.J., Lipperman-Kreda, S., Grube, J.W., 2014. Effects of the performance: a role
analysis. Psychol. Rev. 76 (574), 591.
Shamloo, Z.S., Cox, W.M., 2014. Information-enhancement and goal setting techniques for
increasing adaptive motivation and decreasing urges to drink alcohol. Addict. Behav.
39, 1205–1213.
Smith, D.G., et al., 2014. Enhanced orbitofrontal cortex function and lack of attentional bias to
cocaine cues in recreational stimulant users. Biol. Psychiatry 75, 124–131.
Terrett, G., Mclennan, S.N., Henry, J.D., Biernacki, K., Mercuri, K., Curran, H.V., Rendell, P.G.,
2014. Prospective memory impairment in long-term opiate users. Psychopharmacology
(Berl) 231, 2623–2632.
Trull, T.J., Ebner-Priemer, U.W., 2009. Using experience sampling methods/ecological mo-
mentary assessment (ESM/EMA) in clinical assessment and clinical research: introduction
to the special section. Psychol. Assess. 21 (4), 457–462. http://dx.doi.org/10.1037/
a0017653.
References 89
UNODC, 2012. World Drug Report. 2012. United Nations Publication, Sales No. E.12.XI.1.
Vonmoos, M., Hulka, L.M., Preller, K.H., Minder, F., Baumgartner, M.R., Quednow, B.B.,
2014. Cognitive impairment in cocaine users is drug-induced but partially reversible:
evidence from a longitudinal study. Neuropsychopharmacology 39, 2200–2210.
Vrieze, S.I., Vaidyanathan, U., Hicks, B.M., Iacono, W.G., McGue, M., 2014. The role of con-
straint in the development of nicotine, marijuana, and alcohol dependence in young adult-
hood. Behav. Genet. 44, 14–24.
Wiers, R.W., Eberl, C., Rinck, M., Becker, E.S., Lindenmeyer, J., 2011. Retraining automatic
action tendencies changes alcoholic patients’ approach bias for alcohol and improves treat-
ment outcome. Psychol. Sci. 22, 490–497.
Wiers, R.W., Houben, K., Fadardi, J.S., Van Beek, P., Rhemtulla, M., Cox, W.M., 2015. Al-
cohol cognitive bias modification training for problem drinkers over the web. Addict.
Behav. 40, 21–26.
CHAPTER
Neuroscience of learning
and memory for addiction
medicine: from habit
formation to memory
6
reconsolidation
Mary M. Torregrossa*,1, Jane R. Taylor†
*Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
†
Department of Psychiatry, Yale University, New Haven, CT, USA
1
Corresponding authors: Tel.: +1-412-6245723, e-mail address: [email protected]
Abstract
Identifying effective pharmacological treatments for addictive disorders has remained an elu-
sive goal. Many different classes of drugs have shown some efficacy in preclinical models, but
the number of effective clinical therapeutics has remained stubbornly low. The persistence of
drug use and the high frequency of relapse is at least partly attributable to the enduring ability
of environmental stimuli associated with drug use to maintain behavioral patterns of drug use
and induce craving during abstinence. We propose that stimuli associated with drug use exert
such powerful control over behavior through the development of abnormally strong memories,
and their ability to initiate subconscious sequences of motor actions (habits) that promote
uncontrolled drug use. In this chapter, we will review the evidence suggesting that drugs of
abuse strengthen associations with cues in the environment and facilitate habit formation.
We will also discuss potential mechanisms for disrupting memories associated with drug
use to help improve treatments for addiction.
Keywords
Memory, Cues, Reconsolidation, Habit, Extinction, Relapse, Self-administration, Goal-
directed action

91
92 CHAPTER 6 Learning and memory in addiction
1 INTRODUCTION
1.1 ROLE OF LEARNING AND MEMORY IN ADDICTION
Our brains are designed to learn. Learning about our environments and retrieving
accurate information from memory storage is critical to survival. All organisms to
some degree or another must learn where to find food, how to prepare it, how to find
shelter, and what predators to avoid. A variety of factors can influence how effec-
tively an individual acquires and stores new information, including availability of
attentional resources, motivation, and arousal. Drugs of abuse (at certain doses)
can positively affect all of these factors, increasing attention, motivation, and
arousal, so that the behaviors leading to drug use and the stimuli encountered during
drug exposure are strongly encoded. The ability of drugs of abuse to increase dopa-
mine signaling and the signaling of other neurotransmitter systems involved in learn-
ing and memory accounts for this oft-cited ability of drugs to “hijack” normal brain
systems (Abel and Lattal, 2001; Gipson et al., 2013; Milton and Everitt, 2012;
Nestler, 2013; Torregrossa et al., 2011).
During this period of initial drug use, memories surrounding drug use may be
forming and becoming exceptionally strong, but the drugs are used in a controlled
manner, and consumption is initiated with the goal of experiencing the reinforcing
effects of the drug. At this stage, individuals can readily refrain from drug use as
needed. However, with repeated use, the behaviors associated with consumption
can become automatic or habitual. Indeed, many experienced drug users describe
their drug-taking actions as “ritualistic.” Eventually, behaviors oriented towards
drug use become compulsive, such that use continues even if the individual no longer
feels that the drug is reinforcing or experiences adverse consequences.
Nevertheless, the majority of individuals suffering from an addiction eventually
recognize that they have a problem and will quit and abstain from use for some time.
Unfortunately, most individuals eventually relapse and ultimately endure multiple
cycles of abstinence and relapse throughout their lives. At this point, the strong mem-
ories about the people, places, and things (i.e., cues) associated with drug use can
induce craving or drug “wanting” that promotes relapse (Bossert et al., 2013;
Epstein et al., 2006; Torregrossa et al., 2011). Moreover, these cues may also initiate
the subconscious habitual behaviors associated with obtaining and taking drugs that
further increases the likelihood of relapse (Everitt and Robbins, 2005).
Therefore, the successful treatment of addictive disorders may require an ap-
proach that addresses neurobiological changes to learning and memory systems that
occurs as part of the addictive process. In this review, we will go over evidence sup-
porting the theory that drugs of abuse alter learning and memory, including Pavlov-
ian associative learning and habit formation. In addition, we will discuss factors that
may increase risk for drug-induced alterations in learning and memory. Finally, we
will describe possible approaches for treating addictive disorders by manipulating
learning and memory systems, and potential caveats to those approaches.
2 Drug-induced alterations to learning and memory 93
2 DRUG-INDUCED ALTERATIONS TO LEARNING AND MEMORY

2.1 ASSOCIATIVE LEARNING
2.1.1 Clinical studies
One characteristic of addictive disorders is that substance use becomes more impor-
tant than relationships, work, or other activities. It has been hypothesized that this
shift in choice for drugs over natural rewards may be partially mediated by the com-
peting strength of drug-associated memories that overshadows memories associated
with other rewards. Therefore, one would predict that drug-associated memories are
either encoded more strongly or are retrieved more readily than other forms of mem-
ory. However, whether or not a new drug association forms a stronger memory than a
new memory for a natural reward has not been directly tested clinically. Neverthe-
less, several pieces of indirect evidence exist to suggest that this may true. For ex-
ample, in a study comparing brain response of cocaine-using individuals to controls
when confronted with a sexually arousing stimulus versus a cocaine stimulus the
cocaine-using individuals showed a greatly diminished response to the sexual stim-
ulus relative to controls, but showed robust brain activation when presented with a
cocaine-associated stimulus (Garavan et al., 2000). Thus, cocaine-associated mem-
ories may be so strong that they overshadow those of natural rewards.
Further support for the ability of drug-cue memories to overshadow other mem-
ories comes from studies examining the “overshadowing effect” in drug users. Over-
shadowing is a psychological phenomenon that occurs when learning about one cue
overshadows learning about another cue even when both cues are equally predictive
of reward. Drug users have been shown to exhibit overshadowing of neutral cues by
drug-associated cues, indicating that drug cues can interfere with learning about al-
ternative reinforcers (Freeman et al., 2012a,b). In addition, craving has been associ-
ated with the degree of attentional bias to drug-associated cues (Hogarth et al.,
2003a,b, 2006).
2.1.2 Preclinical studies

The clinical studies described above strongly support the hypothesis that drugs of
abuse engage associative learning processes that lead to the over valuation of
drug-associated cues. Substantial evidence also exists to suggest that similar phe-
nomena occur in animal models of addiction.
First, prior exposure to various drugs of abuse can facilitate subsequent associa-
tive learning about cues predictive of natural rewards, using Pavlovian approach,
conditioned reinforcement, and stimulus discrimination procedures (Hankosky
et al., 2013; Harmer and Phillips, 1998; Olausson et al., 2003, 2004a,b; Shiflett,
2012; Taylor and Horger, 1999; Taylor and Jentsch, 2001). In addition, drugs like
nicotine can enhance motivation to respond for presentation of visual cues (cf.,
Liu et al., 2007; Palmatier et al., 2007).
Moreover, individual differences in innate associative learning ability also asso-

ciate with risk for addiction. For example, in previous studies we have found that
mice with high approach to a magazine delivering food reward specifically during
presentation of a predictive cue (high Pavlovian approach mice), have an impaired
ability to stop responding for alcohol when alcohol is no longer present (impaired
extinction), suggesting that these mice were innately more likely to form strong
memories about drug use (Barker et al., 2012). In addition, several studies from Fla-
gel and colleagues have demonstrated that rats that allocate their behavior towards
cues associated with food reward delivery (sign-trackers), as opposed to spending
their time interacting with the place of food delivery (goal-trackers), are at increased
risk for addiction-like behaviors (Flagel et al., 2008, 2009, 2010). Therefore, individ-
ual differences in appetitive associative learning may predispose individuals to form
strong drug-associated memories that promote the development of addiction.
2.2 TRANSLATING MEMORY TO ACTION

Both individual differences in associative learning and drug-induced enhancement of
associative learning circuits may promote the compulsive use and propensity to re-
lapse that characterizes addiction. However, even with the formation of strong drug-
cue memories, increased attentional bias and craving, ultimately the ability of cues to
stimulate drug seeking actions is critical to maintaining drug abuse. In other words, it
may be possible that environmental cues elicit strong drug memories, but with some
cognitive control it may be possible to inhibit drug taking. However, what if individ-
ual traits or chronic drug exposure increase the translation of memories into drug-
taking actions? Such effects would make abstaining from use even more difficult.
The ability of associative (i.e., Pavlovian) memories to invigorate actions aimed
at obtaining a reinforcer is studied experimentally using the Pavlovian-to-Instrumen-
tal Transfer (PIT) procedure. Similar to associative memory formation, preclinical
studies suggest that exposure to drugs of abuse promotes the expression of PIT.
For example, several studies have found that prior cocaine exposure, particularly
self-administered cocaine, can promote PIT for natural reinforcers, and that cocaine
cues can promote cocaine seeking (LeBlanc et al., 2012, 2013, 2014; Ostlund et al.,
2014). In addition, prior amphetamine exposure can also promote PIT (Shiflett,
2012; Wyvell and Berridge, 2001).
Fewer clinical studies have investigated whether or not PIT is enhanced in
chronic drug users. One recent report suggests that alcohol-dependent subjects dem-
onstrate greater PIT than healthy controls (Garbusow et al., 2014), and presentation
of cigarette packs can induce PIT in smokers (Hogarth et al., 2015). Interestingly,
plain, nonbranded packs, were not able to induce PIT in this study, suggesting that
features of a cue need to be consistent with their predictive relationship with drug
experience to induce PIT (Hogarth et al., 2015).
Additional clinical research is needed to fully elucidate the role of PIT-related
processes in the development of addiction. Moreover, we need to increase our
understanding of how individual differences in propensity for PIT may interact
2 Drug-induced alterations to learning and memory 95
with drug exposure to promote addiction. For example, we have found that mice
with high trait PIT have facilitated habit formation and are more likely to prefer
an alcohol-paired environment even after being shocked in that environment
(Barker et al., 2014). These data suggest that innate differences in PIT may predict
one’s propensity to develop habitual or compulsive behavior. Further research
is needed to determine if innate traits and/or drug exposure promotes PIT and to
determine the neural substrates mediating the abilities of cues to potentiate drug-
taking actions.
2.3 HABIT FORMATION

Drugs of abuse not only promote associative learning processes, and the ability of
cues to invigorate actions, but may also promote the transition from goal-directed
actions to stimulus-response habits (Belin et al., 2013; Everitt and Robbins,
2005). Initially, learning to perform any action is guided by the outcome of that ac-
tion, which is often a reinforcer. However, with repetition or practice, behavior can
become habitual, where responses are induced by antecedent environmental stimuli
and are independent of their association with the outcome. Thus, habitual behaviors
continue even if the reinforcer is no longer valued, the action no longer predicts re-
inforcer delivery, or if the action prevents reinforcer delivery (Balleine and
O’Doherty, 2010). Thus, drug addiction is often conceptualized as a “bad habit” be-
cause drug use persists in the face of adverse consequences and is often triggered by
environmental stimuli (Barker and Taylor, 2014; Belin et al., 2013; Everitt and
Robbins, 2005; O’Tousa and Grahame, 2014; Robbins and Everitt, 1999). Moreover,
drugs of abuse stimulate dopamine release in critical prefrontal cortical and dorsal
striatal brain regions that are necessary for habit formation (Balleine and
O’Doherty, 2010; Barker et al., 2013; Coutureau and Killcross, 2003; Gourley
et al., 2013; Yin and Knowlton, 2006; Yin et al., 2006), allowing for the possibility
that drugs of abuse will strongly regulate both goal-directed actions and habitual re-
sponse strategies.
Indeed there is substantial preclinical evidence to suggest that drugs of abuse pro-
mote the formation of habit. For example, Dickinson and colleagues demonstrated
that a habitual response for an alcohol reinforcer or oral cocaine formed more quickly
than for a food reinforcer (Dickinson et al., 2002; Miles et al., 2003). More recently, a
study by Corbit and colleagues also found that alcohol habits form more rapidly than
a food habit (Corbit et al., 2012). In addition, chronic cocaine or amphetamine ex-
posure can promote habit formation for a nondrug reinforcer (Corbit et al., 2014;
LeBlanc et al., 2013; Nelson and Killcross, 2006, 2013; Nordquist et al., 2007). Even
brief exposure to cocaine in adolescence can promote the formation of habits later in
life (Hinton et al., 2014). Finally, studies have shown that while responding for co-
caine is initially goal-directed, cocaine seeking becomes habitual with sufficient
training (Olmstead et al., 2001; Zapata et al., 2010). However, it should be noted that
all of these studies have been conducted in males, and more research on the effects
of drugs of abuse on the circuitry regulating habits in females is warranted.
For example, using a mouse model that allows dissociation of genetic versus gonadal
sex, we have found that genetic males are more likely to form habits for alcohol than
genetic females (Barker et al., 2010), but females are more likely than males to form
habits for food (Quinn et al., 2007).
In addition, other genetic and environmental factors may also influence habit for-
mation, and thus the progression to addiction. For example, studies in rodent models
have found that prior chronic stress or glucocorticoid exposure results in a more rapid
progression to habitual responding for food (Dias-Ferreira et al., 2009; Gourley et al.,
2012). Moreover, acute stress or acute glucocorticoid exposure + noradrenergic stim-
ulation in human subjects biases behavior toward habitual response strategies
(Schwabe and Wolf, 2009, 2010; Schwabe et al., 2010). Due to the fact that prior
stress exposure is a risk factor for developing addictive disorders, and that acute
stress is a strong driver of continued use and relapse after abstinence, it may be that
stress mediates increased risk and propensity to relapse through actions on corticos-
triatal habit circuitry (Guenzel et al., 2014; See and Waters, 2010; Sinha et al., 2011).
On the other hand, we have recently found that adolescents are resistant to form-
ing ethanol-seeking habits relative to adults, but nevertheless consume much more
ethanol (Serlin and Torregrossa, 2014). Adolescence is a known period of vulnera-
bility to developing substance use disorders, but our results suggest that this is not
due to premature habit development, but rather due to goal-directed reward seeking.
Nevertheless, exposure to drugs of abuse may promote habit development in adult-
hood, as has been shown for juvenile cocaine exposure (Hinton et al., 2014). Inter-
estingly, in the studies examining sex differences in habit formation mentioned
above, while we observed that genetic males formed ethanol-seeking habits faster
than genetic females, females consumed more ethanol in free access conditions
(Barker et al., 2010), indicating females may have had more goal-directed reward
seeking.
In addition, rats with high trait impulsivity that have been shown to exhibit many
addiction-like qualities, including compulsive responding for psychostimulants
(Belin et al., 2008; Dalley et al., 2007), nevertheless demonstrate a delay in the de-
velopment of behavioral control by dorsal lateral striatum dopamine systems
(Murray et al., 2014). Therefore, these animals either use different neural systems
to regulate compulsive drug seeking, or alternatively are highly goal-directed in their
drug seeking behavior. Indeed, drug seeking may involve both habitual and goal-
directed components, as one study has shown that cocaine seeking induced by
weakly associated contextual stimuli was habitual, but that cocaine seeking became
goal-directed in the presence of discrete cues strongly associated cocaine delivery
(Root et al., 2009). Similarly, we have found that habitual food seeking responses
(lever presses) become habitual with extended training, while food approach re-
sponses (food delivery port entries) remained goal-directed (Kimchi et al., 2009).
Moreover, one study found that an alcohol-paired context was sufficient to revert
otherwise goal-directed food seeking to habitual control, further indicating that drug
exposure and drug-associated cues can promote habitual response strategies (Ostlund
et al., 2010).
3 Learning and memory systems as addiction medicine 97
Based on our current state of knowledge, drug addiction most likely involves both
highly goal-directed components involved in drug seeking, but that relapse after ab-
stinence or loss of control over use, such as in a binge, is due to reversion to habitual
behavior. Therefore, treatment strategies that can either reduce the ability of drug-
paired stimuli to induce habitual response patterns, or treatments that help individ-
uals regain cognitive control over their drug seeking may improve addiction therapy.
3 LEARNING AND MEMORY SYSTEMS AS ADDICTION

MEDICINE
3.1 OVERVIEW
As described above, cues associated with drugs of abuse can become strong drivers
of behavior and contribute to the development of addiction. Therefore, identifying
approaches that reduce the strength of drug-associated memories could aid in the
treatment of addiction at multiple levels. Interfering with the associative memories
directly, that is disrupting the associations between environmental cues and drug use,
is one strategy that has received increased attention over the past several years.
Traditionally, acquisition, consolidation, and retrieval have been considered the
three cornerstones of the learning and memory process. However, more recently,
research has examined what happens to memories during and after retrieval. First,
several studies have established that in the process of retrieving information
from long-term storage the memory becomes “destabilized.” That is, the molecular
mechanisms supporting the memory are reactivated and the memory becomes labile
and subject to disruption. Once the memory is destabilized, it is then restored, or
“restabilized” in long-term memory in a process termed reconsolidation, which
requires many of the same molecular mechanisms essential for initial consolidation
(Duvarci and Nader, 2004; Finnie and Nader, 2012; Nader et al., 2000; Taylor et al.,
2009; Tronson and Taylor, 2007). Every time a drug-associated memory is retrieved
and reconsolidated into long-term memory the reconsolidation process may also be
stronger resulting in progressively more invasive drug-associated memories with re-
peated use (Lee, 2008; Sara, 2000; Sorg, 2012; Tronson and Taylor, 2007; Tronson
et al., 2006). Ultimately, this may make drug-associated memories particularly dif-
ficult to disrupt, but amenable to pharmacological methods for inhibiting the recon-
solidation process. In addition, exposure to cues in the absence of drug, either
repeatedly or for a prolonged period of time, can lead to formation of a new
“extinction” memory. An extinction memory is a new memory that a cue is not as-
sociated with drug use, and this new memory interferes with the expression behaviors
associated with the original memory (Holmes and Quirk, 2010; Peters et al., 2009;
Quirk and Mueller, 2008; Taylor et al., 2009; Torregrossa and Taylor, 2012).
Pharmacological manipulations can affect all phases of memory, including ex-
tinction and reconsolidation processes, to either enhance or strengthen the memory
or to make it weaker or even forgotten. In the next sections, we will discuss some of
the behavioral and pharmacological approaches that show promise for potentially
improving the treatment of addictive disorders.
3.2 RECONSOLIDATION
Several reviews have discussed the molecular mechanisms underlying the reconso-
lidation of memories, including memories associated with exposure to drugs of abuse
(Lattal and Wood, 2013; Milton and Everitt, 2010; Sorg, 2012; Taylor et al., 2009;
Torregrossa and Taylor, 2012). In this section, we will focus on clinically available
pharmacological agents with substantial supporting preclinical data supporting their
development as memory-based addiction treatments.
One of the most widely studied manipulations of reconsolidation, both preclini-
cally and clinically, is the inhibition of b-adrenergic receptors (bARs). Notably, the
clinically available bAR antagonist propranolol, administered systemically in ani-
mal models, can interfere with drug memory reconsolidation (Bernardi et al.,
2006; Milton et al., 2008). Therefore, propranolol has the potential to be a clinically
viable treatment for addiction. Indeed, one pilot clinical study in cocaine-dependent
subjects indicates that under certain conditions postretrieval propranolol can reduce
subsequent cocaine craving (Saladin et al., 2013). Several other clinical studies have
supported the potential utility of propranolol-induced disruption of reconsolidation
in fear-associated disorders, such as posttraumatic stress disorder (Soeter and
Kindt, 2011).
In addition to bAR antagonists, several other classes of compounds are approved
for use in humans and have demonstrated some ability to disrupt the reconsolidation
of drug-associated memories in rodent models. For example, the anxiolytic GABAa
receptor agonist midazolam can disrupt reconsolidation of a morphine conditioned
place preference memory (Robinson and Franklin, 2010; Robinson et al., 2011).
However, the efficacy of midazolam seems to be highly dependent on the strength
and age of the memory, and the physiological state of the animal, including being
morphine dependent or under stress (Bustos et al., 2010; Robinson and Franklin,
2010; Robinson et al., 2011). Therefore, midazolam may only be effective for very
weak and recent memories that are easily destabilized. Further, preclinical research
is needed to determine if midazolam is effective in drug self-administration models
and in clinically relevant situations, such as disrupting very strong and well-
established memories associated with drug use.
Finally, several studies have pointed toward the effectiveness of inhibiting the
mTOR signaling pathway with rapamycin to interfere with drug memory reconsoli-
dation (Barak et al., 2013; Lin et al., 2014; Shi et al., 2014). mTOR signaling
regulates protein translation, cell growth, and mitochondrial activity. Targeting com-
ponents of the mTOR signaling pathway has been of great clinical interest, and rapa-
mycin has been approved for use in humans for a number of years (Lamming, 2014).
Importantly, rapamycin can be given systemically postmemory reactivation to disrupt
reconsolidation allowing the possibility of using rapamycin as a targeted treatment for
maladaptive memory-based disorders (Glover et al., 2010; Mac Callum et al., 2013).
As with any reconsolidation-based treatment for addiction, rapamycin would have to

be given after reactivation of the specific memories to be targeted in a controlled en-
vironment. To date, neither rapamycin, midazolam, or any other compound proposed
to disrupt reconsolidation has been tested clinically in the treatment of addiction, but
we anticipate a proliferation of these studies in the future given the availability of clin-
ically approved compounds.
3.3 EXTINCTION
In addition to reconsolidation disruption, drug-associated memories can also be
weakened through the process of extinction. Clinical studies have demonstrated that
extinction can reduce some of the conditioned physiological effects induced by drug
cues and reduces reported subjective levels of craving (Foltin and Haney, 2000;
O’Brien et al., 1993). However, clinical cue extinction approaches have generally
been ineffective (Conklin and Tiffany, 2002). Therefore, more recent research has
focused on potential pharmacological manipulations that might be used in conjunc-
tion with extinction to help individuals maintain abstinence. For example, much
attention has been given to enhancing the consolidation of extinction learning with
the cognitive enhancer D-cycloserine (DCS) (Davis et al., 2006; Myers and Carlezon,
2012).
DCS is a positive modulator of NMDA receptor signaling, acting as a partial
agonist at the glycine site of the receptor. DCS can enhance learning in a variety
of paradigms, including extinction of drug-associated memories (Botreau et al.,
2006; Nic Dhonnchadha et al., 2010; Paolone et al., 2009; Thanos et al., 2009,
2011; Torregrossa et al., 2010). DCS is safe to give clinically and has been assessed
in a number of studies in human subjects. DCS has proven effective in some anxiety
disorders, including specific phobias (Ressler et al., 2004), and has shown some
promise in reducing cue reactivity in smokers (Santa Ana et al., 2009). However,
the majority of clinical studies have not found DCS to be an effective adjunct to
extinction-based therapy, including studies in cocaine- and alcohol-dependent sub-
jects (Hofmann et al., 2012; Price et al., 2012; Watson et al., 2011). Nevertheless,
no clinical studies have yet administered DCS after the extinction sessions to assure
that individuals achieve significant levels of extinction learning prior to receiving this
memory-enhancing drug. Therefore, it is possible that in these studies competing
reconsolidation processes were also being enhanced by DCS treatment, masking any
potential benefit. Indeed, depending on the conditions DCS can either enhance
reconsolidation or enhance extinction (Lee et al., 2006). Therefore, careful design of
clinical studies is warranted. Preferably, other targets will be found for extinction en-
hancement that do not also possess the potential to strengthen memory reconsolidation.
To date the majority of other pharmacological agents tested for extinction enhanc-
ing effects are other cognitive enhancing agents also acting on the glycine site of the
NMDA receptor, such as D-serine, or AMPA receptor potentiators. D-serine is more
potent than DCS, and has been shown to facilitate extinction in a number of studies
(Hafenbreidel et al., 2014; Hammond et al., 2013; Kelamangalath and Wagner,
2010). In addition, the AMPA receptor positive allosteric modulator PEPA also
produces cognitive enhancing effects and can facilitate the extinction of instrumental
cocaine seeking in a self-administration paradigm (LaLumiere et al., 2010, 2012).
In fear conditioning paradigms, the effects of PEPA are selective to extinction, not
enhancing the reconsolidation of fear memories (Yamada et al., 2009). Therefore,
PEPA may overcome the problem with DCS, that addictive memories may be unin-
tentionally strengthened through reconsolidation mechanisms. However, the ability
of PEPA to affect drug memory reconsolidation has not yet been tested.
Finally, another promising class of compounds that may selectively enhance ex-
tinction learning are histone deacetylase (HDAC) inhibitors. Gene expression is
tightly controlled by the regulation of chromatin in the nucleus. Chromatin consists
of DNA wrapped around histone proteins, and modification of histones by acetyla-
tion and methylation can condense or relax chromatin around specific genes to allow
transcription. Histone modifications are dynamic and are known to regulate learning
and memory processes. Histone acetylation generally creates a permissive gene tran-
scription state, and maintaining histone acetylation with HDAC inhibitors can en-
hance learning and memory (Jarome and Lubin, 2013; Lattal and Wood, 2013;
Lubin et al., 2011). Nonspecific HDAC inhibition with sodium butyrate given after
cocaine conditioned place preference extinction sessions facilitates extinction and
reduces subsequent reinstatement of preference induced by re-exposure to cocaine
(Malvaez et al., 2010). However, sodium butyrate can potentially enhance associa-
tive learning about cocaine (Itzhak et al., 2013; Raybuck et al., 2013), suggesting that
the administration of sodium butyrate would have to be closely monitored in clinical
settings. A more specific HDAC3 inhibitor, however, holds promise as a potential
extinction enhancing agent that can promote extinction and reduce reinstatement
of a conditioned place preference for cocaine (Malvaez et al., 2013). Future studies
in self-administration models will provide further evidence to support testing mod-
ulators of histone acetylation in clinical studies.
3.4 RESTORING GOAL-DIRECTED BEHAVIOR

Finally, it may be possible to interfere with the expression of habitual and compul-
sive drug use to help individuals maintain abstinence. Theoretically, reducing the
strength of cue-drug associative memories through either reconsolidation or extinc-
tion mechanisms will disrupt the ability of these cues to induce habitual patterns of
behavior (Fig. 1). However, little research has been conducted to directly test
whether or not memory manipulations interfere with habitual behaviors or if habit
memories are capable of disruption. To date, the majority of studies have assessed
drug place preference or operant self-administration under conditions that do not re-
sult in habit formation (Corbit et al., 2012; Economidou et al., 2009; Olmstead et al.,
2001; Zapata et al., 2010). Therefore, it is difficult to know if any of the manipula-
tions listed above are effective under conditions of habitual or compulsive drug seek-
ing. In addition, it is only possible to assess habit if the action-outcome contingency
or value of the outcome is disrupted. Thus, in animal studies where the value of the
Model for reconsolidation interference as addiction medicine

Destabilization Labile Reconsolidation Amnestic
drug-cue agent
memory
Predication
error signal
Consolidated Drug seeking, Abstinence,

drug-cue habitual behavior goal-directed
memory behavior?
FIGURE 1
The destabilization–restabilization process in cocaine-cue memory reconsolidation.
A theoretical framework for the impact of prediction error on destabilization and
reconsolidation of a cocaine-cue memory and subsequent effects on drug seeking and
expression of habitual behaviors.
drug presumably remains high, restoration of goal-directed behavior might be pre-

dicted to increase rather decrease drug seeking. There is, therefore, a need for more
animal studies testing whether memory manipulations or manipulations targeting
habit circuitry can reduce drug seeking in models where the drug is associated with
adverse consequences (e.g., foot shock). One study has found that the cystine pro-
drug, n-acetylcysteine, which can promote extinction of drug seeking (Zhou and
Kalivas, 2008), and has demonstrated some clinical efficacy in addiction treatment
(cf., LaRowe et al., 2013; Mousavi et al., 2015), can also restore goal-directed food
seeking behaviors after cocaine exposure (Corbit et al., 2014). Additional studies are
needed to further explore the relationship between memory modulating agents and
the expression of habitual behaviors.
Few studies have explicitly tested whether or not restoring goal-directed behavior
can reduce drug seeking or treat addiction. However, using a compulsive drug seek-
ing model where rats are periodically punished for drug seeking with a foot shock,
Economidou and colleagues demonstrated that treatment with the norepinephrine re-
uptake inhibitor atomoxetine reduced compulsive cocaine seeking (Economidou
et al., 2009). In addition, systemic administration of the dopamine D2 receptor partial
agonist aripiprazole, also reduces compulsive cocaine seeking. Thus, activating D2
receptors may help reduce habitual or compulsive drug use and similar effects may
also be observed by antagonizing dopamine D1 receptors (Barker et al., 2013; Nelson
and Killcross, 2013). Unfortunately, clinical laboratory studies of smokers or cocaine
users have not found any therapeutic potential for D2 agonists or D1 antagonists
(Haney et al., 1998, 2001, 2011; Lofwall et al., 2014). However, it should be noted
that in these studies the value of cocaine or cigarettes was not explicitly manipulated,
so if goal-directed behavior was restored, individuals may have maintained or in-
creased goal-directed drug seeking. Therefore, any treatments aimed at interfering
with habitual behavior will have to be given in conjunction with explicit behavioral
treatment paradigms that emphasize the negative consequences of drug use.
4 SPECIAL CONSIDERATIONS FOR MEMORY MANIPULATIONS

IN THE TREATMENT OF ADDICTION
4.1 OVERVIEW
The sections above described many examples of potentially clinically applicable
treatments for addictive disorders based on altering learning and memory systems.
However, all of these approaches rely on combining some sort of behavioral inter-
vention or laboratory manipulation with the administration of the therapeutic agent.
Treatments based on learning and memory cannot be given as a daily pill as is typical
for treatments of other chronic disorders. In some circumstances, this may be an ad-
vantage of memory-based treatments as concerns about medication compliance and
side effects induced by chronic use would be mitigated. However, memory-based
strategies do require substantial experimentation to determine the ideal conditions
for memory disruption, including duration of cue exposure, timing of medication,
frequency of intervention, to name a few. The sections below will briefly describe
some of the considerations that need to be addressed for the successful implemen-
tation of memory-based interventions as addiction medicine.
4.2 TARGETING DRUG MEMORY DESTABILIZATION MECHANISMS?

An additional possible approach would be to use behavioral methods to selectively
enhance memory destabilization to make a drug-cue memory more sensitive to sub-
sequent disruption by amnestic agents. As discussed above, according to theories of
reconsolidation, a drug-CS memory may become destabilized by a CS reminder
(memory reactivation). Destabilization pushes the CS to a labile state, in which
the memory is subject to modification prior to being restabilized. Memory destabi-
lization is a fundamental constraint in reconsolidation that has been only studied
within the context of nondrug memories. There has been little work to establish
the neurobehavioral triggers of cocaine memory destabilization, but conditions that
require new information to be integrated into the existing memory appear to be im-
portant (cf., Lee, 2009; Sevenster et al., 2013; Tronson and Taylor, 2013). Indeed,
we, and others, have recently hypothesized that a prediction error (PE) triggered
by a difference between predicted outcomes and the actual outcomes experienced
specifically engages destabilization (Exton-McGuinness et al., 2015). Expectancy-
based error correction processes are common to most theories of associative
learning, and are argued to be a factor in drug-associated learning mechanisms
(cf., Corlett and Taylor, 2013; Corlett et al., 2009; Tronson and Taylor, 2013). Inter-
estingly, cocaine use disorders have been associated with possible deficits in nega-
tive PE signals (Parvaz et al., 2015) and thus manipulating PE directly in addicts may
aid in abstinence. If, for example, memory destabilization could be enhanced,
amnestic agents could be used to more persistently or effectively block memory
restabilization. We hypothesize that behavioral interventions could be used to en-
hance PEs to render a CS-drug memory labile and subject to modifications to reduce
4 Special considerations for memory manipulations 103
the strength of the memory. We have previously shown that the strength of a cocaine-
cue memory can be reduced by administering an amnestic agent following reactiva-
tion of the cocaine-cue memory in the absence of the US, which may result in a
negative PE (Sanchez et al., 2010; Wan et al., 2014). Therefore, we hypothesize that
the ability to behaviorally induce and/or enhance the destabilization of cocaine-cue
memories through PE manipulation could be a key factor for the efficacy of subse-
quent or combined pharmacological therapies that aim to disrupt reconsolidation
process and weaken maladaptive drug memories (see Fig. 1).
4.3 MEMORY SPECIFICITY AND BOUNDARY CONDITIONS

One concern often expressed about using reconsolidation inhibitors to treat any dis-
order is the possibility that other important memories will also be disrupted. This is
certainly a valid concern, and any manipulation used to disrupt reconsolidation
should be thoroughly tested in animal models for memory specificity. However,
in general, reconsolidation disruption seems to be fairly specific to the manipulated
memory, with studies in fear conditioning demonstrating that protein synthesis inhi-
bition only disrupts reconsolidation of reactivated conditioned stimulus memories,
but not memories for other conditioned stimuli that were not reactivated (Debiec
et al., 2006). Moreover, we have seen similar effects for a cocaine-associated mem-
ory, where disruption of memory reconsolidation with PKA inhibition, did not affect
the ability of the rats to remember to press the lever in a test of cocaine-primed re-
instatement (Sanchez et al., 2010). In addition, several studies have indicated remote
or strongly encoded memories are harder to destabilize and are less subject to recon-
solidation disruption than newer memories (Bustos et al., 2009; Inda et al., 2011;
Raybuck and Lattal, 2014). Therefore, established biographical memories, for exam-
ple, may be unlikely to be destabilized and disrupted by reconsolidation
manipulations.
On the flip side, one could argue that memories associated with drugs of abuse are
often very strongly encoded, and are remote after years of use. Individuals may also
have many memories associated with drug use, such that a more generalized disrup-
tion of all drug memories would be desired. Future studies are certainly warranted to
address these issues in the addiction field.
4.4 PERSISTENCE OF EFFECTS

A critical potential limitation to reconsolidation and extinction manipulations is that
any positive effects that are observed are unlikely to be long lasting. Persistence of
effects is certainly a concern for extinction-based therapies, as extinction is known to
be a temporary phenomenon with the expression of the original memory returning
with time: a process known as spontaneous recovery, and with exposure to a context
not associated with extinction: a process known as renewal (Bouton et al., 2006;
Torregrossa et al., 2010, 2013). In addition, while reconsolidation disruption is the-
oretically a more permanent manipulation, the persistence of reconsolidation
manipulations is often not assessed. Moreover, memories can easily be

re-established or new memories formed with re-exposure to the drug of abuse. There-
fore, successful addiction treatment may require multiple intermittent memory ma-
nipulation sessions to maintain abstinence, and to potentially address new memories
over time. Developing and implementing a maintenance treatment plan is likely to be
critical for the long-term success of memory-based therapies for addiction.
4.5 RESTORATION OF GOAL-DIRECTED DRUG SEEKING?

Finally, as mentioned above, efforts to inhibit habitual patterns of drug use or to
regain goal-directed control of behavior must be carefully considered. If individuals
do not perceive continued drug use as problematic, then enhancing goal-directedness
is likely to just maintain or even increase drug use. For example, adolescents
responding for alcohol display highly goal-directed motivation for much larger quan-
tities of alcohol than adults expressing habitual behavior (Serlin and Torregrossa,
2014). Therefore, manipulations aimed at disrupting habit in human subjects will
likely need to be conducted in conjunction either with agents that reduce the value
of drug use or behavioral therapies that emphasize the negative consequences of con-
tinued use. More research is needed to determine the effectiveness of these ap-
proaches. Nevertheless, reconsolidation- or extinction-based therapies that
interfere with stimulus-response associations may still help individuals refrain for
initiating use or engaging in uncontrolled use, such as in a binge.

Considering the burden of addictive disorders on society and the scarcity of effective
treatments, new approaches for addiction medicine are certainly warranted. As
reviewed above, drugs of abuse produce profound effects on the brain’s learning
and memory systems that control motivated behavior (Jentsch and Taylor, 1999).
Identifying manipulations that can reverse the strong hold drug-associated memories
have on behavior could greatly improve rates of abstinence and help individuals
regain control over intake. Preclinical studies largely support the use of memory-
based approaches to treat addiction, and several clinical studies suggest the potential
utility of these treatment strategies. We argue that one novel approach would be to
enhance memory lability, by triggering memory destabilization, thereby rendering
cocaine-cue memories more sensitive to subsequent disruption by amnestic agents,
and consequently to persistently reduce relapse triggered by drug-cue memories.
Nevertheless, substantial research is still needed to determine the conditions under
which memory manipulations are most effective, how long these manipulations
maintain effectiveness, and to ensure that unintentional increases in drug memory
strength or goal-directed drug taking do not occur.
References 105
REFERENCES
Abel, T., Lattal, K.M., 2001. Molecular mechanisms of memory acquisition, consolidation and
retrieval. Curr. Opin. Neurobiol. 11, 180–187.
Balleine, B.W., O’Doherty, J.P., 2010. Human and rodent homologies in action control: cor-
ticostriatal determinants of goal-directed and habitual action. Neuropsychopharmacology
35, 48–69.
Barak, S., Liu, F., Ben Hamida, S., Yowell, Q.V., Neasta, J., Kharazia, V., Janak, P.H.,
Ron, D., 2013. Disruption of alcohol-related memories by mTORC1 inhibition prevents
relapse. Nat. Neurosci. 16, 1111–1117.
Barker, J.M., Taylor, J.R., 2014. Habitual alcohol seeking: modeling the transition from casual
drinking to addiction. Neurosci. Biobehav. Rev. 47, 281–294.
Barker, J.M., Torregrossa, M.M., Arnold, A.P., Taylor, J.R., 2010. Dissociation of genetic and
hormonal influences on sex differences in alcoholism-related behaviors. J. Neurosci.
30, 9140–9144.
Barker, J.M., Torregrossa, M.M., Taylor, J.R., 2012. Low prefrontal PSA-NCAM confers risk
for alcoholism-related behavior. Nat. Neurosci. 15, 1356–1358.
Barker, J.M., Torregrossa, M.M., Taylor, J.R., 2013. Bidirectional modulation of infralimbic
dopamine D1 and D2 receptor activity regulates flexible reward seeking. Front. Neurosci.
7, 126.
Barker, J.M., Zhang, H., Villafane, J.J., Wang, T.L., Torregrossa, M.M., Taylor, J.R., 2014.
Epigenetic and pharmacological regulation of 5HT3 receptors controls compulsive etha-
nol seeking in mice. Eur. J. Neurosci. 39, 999–1008.
Belin, D., Mar, A.C., Dalley, J.W., Robbins, T.W., Everitt, B.J., 2008. High impulsivity pre-
dicts the switch to compulsive cocaine-taking. Science 320, 1352–1355.
Belin, D., Belin-Rauscent, A., Murray, J.E., Everitt, B.J., 2013. Addiction: failure of control
over maladaptive incentive habits. Curr. Opin. Neurobiol. 23, 564–572.
Bernardi, R.E., Lattal, K.M., Berger, S.P., 2006. Postretrieval propranolol disrupts a cocaine
conditioned place preference. Neuroreport 17, 1443–1447.
Bossert, J.M., Marchant, N.J., Calu, D.J., Shaham, Y., 2013. The reinstatement model of drug
relapse: recent neurobiological findings, emerging research topics, and translational re-
search. Psychopharmacology (Berl.) 229, 453–476.
Botreau, F., Paolone, G., Stewart, J., 2006. D-Cycloserine facilitates extinction of a cocaine-
induced conditioned place preference. Behav. Brain Res. 172, 173–178.
Bouton, M.E., Westbrook, R.F., Corcoran, K.A., Maren, S., 2006. Contextual and temporal
modulation of extinction: behavioral and biological mechanisms. Biol. Psychiatry
60, 352–360.
Bustos, S.G., Maldonado, H., Molina, V.A., 2009. Disruptive effect of midazolam on fear
memory reconsolidation: decisive influence of reactivation time span and memory age.
Bustos, S.G., Giachero, M., Maldonado, H., Molina, V.A., 2010. Previous stress attenuates
the susceptibility to Midazolam’s disruptive effect on fear memory reconsolidation:
influence of pre-reactivation D-cycloserine administration. Neuropsychopharmacology
35, 1097–1108.
Conklin, C.A., Tiffany, S.T., 2002. Applying extinction research and theory to cue-exposure
addiction treatments. Addiction 97, 155–167.
Corbit, L.H., Nie, H., Janak, P.H., 2012. Habitual alcohol seeking: time course and the con-
tribution of subregions of the dorsal striatum. Biol. Psychiatry 72, 389–395.
Corbit, L.H., Chieng, B.C., Balleine, B.W., 2014. Effects of repeated cocaine exposure on
habit learning and reversal by N-acetylcysteine. Neuropsychopharmacology
39, 1893–1901.
Corlett, P.R., Taylor, J.R., 2013. The translational potential of memory reconsolidation. In:
Alberini, C. (Ed.), Memory Reconsolidation. Elsevier Press, New York, NY, pp. 273–292.
Corlett, P.R., Krystal, J.H., Taylor, J.R., Fletcher, P.C., 2009. Why do delusions persist? Front.
Hum. Neurosci. 3, 12.
Coutureau, E., Killcross, S., 2003. Inactivation of the infralimbic prefrontal cortex reinstates
goal-directed responding in overtrained rats. Behav. Brain Res. 146, 167–174.
Dalley, J.W., Fryer, T.D., Brichard, L., Robinson, E.S.J., Theobald, D.E.H., Lääne, K., Peña, Y.,
Murphy, E.R., Shah, Y., Probst, K., Abakumova, I., Aigbirhio, F.I., Richards, H.K.,
Hong, Y., Baron, J.-C., Everitt, B.J., Robbins, T.W., 2007. Nucleus accumbens D2/3
receptors predict trait impulsivity and cocaine reinforcement. Science 315, 1267–1270.
Davis, M., Ressler, K., Rothbaum, B.O., Richardson, R., 2006. Effects of D-cycloserine on
extinction: translation from preclinical to clinical work. Biol. Psychiatry 60, 369–375.
Debiec, J., Doyère, V., Nader, K., Ledoux, J.E., 2006. Directly reactivated, but not indirectly
reactivated, memories undergo reconsolidation in the amygdala. Proc. Natl. Acad. Sci.
U. S. A. 103, 3428–3433.
Dias-Ferreira, E., Sousa, J.C., Melo, I., Morgado, P., Mesquita, A.R., Cerqueira, J.J.,
Costa, R.M., Sousa, N., 2009. Chronic stress causes frontostriatal reorganization and
affects decision-making. Science 325, 621–625.
Dickinson, A., Wood, N., Smith, J.W., 2002. Alcohol seeking by rats: action or habit? Q. J.
Exp. Psychol. B 55, 331–348.
Duvarci, S., Nader, K., 2004. Characterization of fear memory reconsolidation. J. Neurosci.
24, 9269–9275.
Economidou, D., Pelloux, Y., Robbins, T.W., Dalley, J.W., Everitt, B.J., 2009. High impul-
sivity predicts relapse to cocaine-seeking after punishment-induced abstinence. Biol. Psy-
chiatry 65, 851–856.
Epstein, D.H., Preston, K.L., Stewart, J., Shaham, Y., 2006. Toward a model of drug relapse:
an assessment of the validity of the reinstatement procedure. Psychopharmacology (Berl.)
189, 1–16.
Everitt, B.J., Robbins, T.W., 2005. Neural systems of reinforcement for drug addiction: from
actions to habits to compulsion. Nat. Neurosci. 8, 1481–1489.
Exton-McGuinness, M.T.J., Lee, J.L.C., Reichelt, A.C., 2015. Updating memories—the role
of prediction errors in memory reconsolidation. Behav. Brain Res. 278, 375–384.
Finnie, P.S.B., Nader, K., 2012. The role of metaplasticity mechanisms in regulating memory
destabilization and reconsolidation. Neurosci. Biobehav. Rev. 36, 1667–1707.
Flagel, S.B., Watson, S.J., Akil, H., Robinson, T.E., 2008. Individual differences in the attri-
bution of incentive salience to a reward-related cue: influence on cocaine sensitization.
Behav. Brain Res. 186, 48–56.
Flagel, S.B., Akil, H., Robinson, T.E., 2009. Individual differences in the attribution of incen-
tive salience to reward-related cues: implications for addiction. Neuropharmacology
56 (Suppl. 1), 139–148.
Flagel, S.B., Robinson, T.E., Clark, J.J., Clinton, S.M., Watson, S.J., Seeman, P., Phillips, P.E.
M., Akil, H., 2010. An animal model of genetic vulnerability to behavioral disinhibition
and responsiveness to reward-related cues: implications for addiction.
References 107
Foltin, R.W., Haney, M., 2000. Conditioned effects of environmental stimuli paired with
smoked cocaine in humans. Psychopharmacology (Berl.) 149, 24–33.
Freeman, T.P., Morgan, C.J.A., Beesley, T., Curran, H.V., 2012a. Drug cue induced oversha-
dowing: selective disruption of natural reward processing by cigarette cues amongst ab-
stinent but not satiated smokers. Psychol. Med. 42, 161–171.
Freeman, T.P., Morgan, C.J.A., Pepper, F., Howes, O.D., Stone, J.M., Curran, H.V., 2012b.
Associative blocking to reward-predicting cues is attenuated in ketamine users but can
be modulated by images associated with drug use. Psychopharmacology (Berl.)
225, 41–50.
Garavan, H., Pankiewicz, J., Bloom, A., Cho, J.K., Sperry, L., Ross, T.J., Salmeron, B.J.,
Risinger, R., Kelley, D., Stein, E.A., 2000. Cue-induced cocaine craving: neuroanatomical
specificity for drug users and drug stimuli. Am. J. Psychiatry 157, 1789–1798.
Garbusow, M., Schad, D.J., Sommer, C., Jünger, E., Sebold, M., Friedel, E., Wendt, J.,
Kathmann, N., Schlagenhauf, F., Zimmermann, U.S., Heinz, A., Huys, Q.J.M., Rapp, M.A.,
2014. Pavlovian-to-instrumental transfer in alcohol dependence: a pilot study.
Neuropsychobiology 70, 111–121.
Gipson, C.D., Kupchik, Y.M., Kalivas, P.W., 2013. Rapid, transient synaptic plasticity in ad-
diction. Neuropharmacology 76, 276–286.
Glover, E.M., Ressler, K.J., Davis, M., 2010. Differing effects of systemically administered
rapamycin on consolidation and reconsolidation of context vs. cued fear memories. Learn.
Mem. 17, 577–581.
Gourley, S.L., Swanson, A.M., Jacobs, A.M., Howell, J.L., Mo, M., Dileone, R.J., Koleske, A.J.,
Taylor, J.R., 2012. Action control is mediated by prefrontal BDNF and glucocorticoid
receptor binding. Proc. Natl. Acad. Sci. U. S. A. 109, 20714–20719.
Gourley, S.L., Olevska, A., Gordon, J., Taylor, J.R., 2013. Cytoskeletal determinants of
stimulus-response habits. J. Neurosci. 33, 11811–11816.
Guenzel, F.M., Wolf, O.T., Schwabe, L., 2014. Sex differences in stress effects on response
and spatial memory formation. Neurobiol. Learn. Mem. 109, 46–55.
Hafenbreidel, M., Rafa Todd, C., Twining, R.C., Tuscher, J.J., Mueller, D., 2014. Bidirectional
effects of inhibiting or potentiating NMDA receptors on extinction after cocaine self-
administration in rats. Psychopharmacology (Berl.) 231, 4585–4594.
Hammond, S., Seymour, C.M., Burger, A., Wagner, J.J., 2013. D-Serine facilitates the effec-
tiveness of extinction to reduce drug-primed reinstatement of cocaine-induced conditioned
place preference. Neuropharmacology 64, 464–471.
Haney, M., Foltin, R.W., Fischman, M.W., 1998. Effects of pergolide on intravenous cocaine
self-administration in men and women. Psychopharmacology (Berl.) 137, 15–24.
Haney, M., Ward, A.S., Foltin, R.W., Fischman, M.W., 2001. Effects of ecopipam, a selective
dopamine D1 antagonist, on smoked cocaine self-administration by humans. Psychophar-
macology (Berl.) 155, 330–337.
Haney, M., Rubin, E., Foltin, R.W., 2011. Aripiprazole maintenance increases smoked cocaine
self-administration in humans. Psychopharmacology (Berl.) 216, 379–387.
Hankosky, E.R., Kofsky, N.M., Gulley, J.M., 2013. Age of exposure-dependent effects of am-
phetamine on behavioral flexibility. Behav. Brain Res. 252, 117–125.
Harmer, C.J., Phillips, G.D., 1998. Enhanced appetitive conditioning following repeated pre-
treatment with D-amphetamine. Behav. Pharmacol. 9, 299–308.
Hinton, E.A., Wheeler, M.G., Gourley, S.L., 2014. Early-life cocaine interferes with BDNF-
mediated behavioral plasticity. Learn. Mem. 21, 253–257.
Hofmann, S.G., Hüweler, R., MacKillop, J., Kantak, K.M., 2012. Effects of D-cycloserine on
craving to alcohol cues in problem drinkers: preliminary findings. Am. J. Drug Alcohol
Abuse 38, 101–107.
Hogarth, L., Dickinson, A., Duka, T., 2003a. Discriminative stimuli that control instrumental
tobacco-seeking by human smokers also command selective attention. Psychopharmacol-
ogy (Berl.) 168, 435–445.
Hogarth, L.C., Mogg, K., Bradley, B.P., Duka, T., Dickinson, A., 2003b. Attentional orienting
towards smoking-related stimuli. Behav. Pharmacol. 14, 153–160.
Hogarth, L., Dickinson, A., Hutton, S.B., Elbers, N., Duka, T., 2006. Drug expectancy is nec-
essary for stimulus control of human attention, instrumental drug-seeking behaviour and
subjective pleasure. Psychopharmacology (Berl.) 185, 495–504.
Hogarth, L., Maynard, O.M., Munafò, M.R., 2015. Plain cigarette packs do not exert Pavlovian
to instrumental transfer of control over tobacco-seeking. Addiction 110, 174–182.
Holmes, A., Quirk, G.J., 2010. Pharmacological facilitation of fear extinction and the search
for adjunct treatments for anxiety disorders—the case of yohimbine. Trends Pharmacol.
Sci. 31, 2–7.
Inda, M.C., Muravieva, E.V., Alberini, C.M., 2011. Memory retrieval and the passage of time:
from reconsolidation and strengthening to extinction. J. Neurosci. 31, 1635–1643.
Itzhak, Y., Liddie, S., Anderson, K.L., 2013. Sodium butyrate-induced histone acetylation
strengthens the expression of cocaine-associated contextual memory. Neurobiol. Learn.
Mem. 102, 34–42.
Jarome, T.J., Lubin, F.D., 2013. Histone lysine methylation: critical regulator of memory and
behavior. Rev. Neurosci. 24, 375–387.
Jentsch, J.D., Taylor, J.R., 1999. Impulsivity resulting from frontostriatal dysfunction in drug
abuse: implications for the control of behavior by reward-related stimuli. Psychopharma-
cology (Berl.) 146, 373–390.
Kelamangalath, L., Wagner, J.J., 2010. D-serine treatment reduces cocaine-primed reinstate-
ment in rats following extended access to cocaine self-administration. Neuroscience
169, 1127–1135.
Kimchi, E.Y., Torregrossa, M.M., Taylor, J.R., Laubach, M., 2009. Neuronal correlates of in-
strumental learning in the dorsal striatum. J. Neurophysiol. 102, 475–489.
LaLumiere, R.T., Niehoff, K.E., Kalivas, P.W., 2010. The infralimbic cortex regulates the
consolidation of extinction after cocaine self-administration. Learn. Mem. 17, 168–175.
LaLumiere, R.T., Smith, K.C., Kalivas, P.W., 2012. Neural circuit competition in cocaine-
seeking: roles of the infralimbic cortex and nucleus accumbens shell. Eur. J. Neurosci.
35, 614–622.
Lamming, D.W., 2014. Diminished mTOR signaling: a common mode of action for endocrine
longevity factors. SpringerPlus 3, 735.
LaRowe, S.D., Kalivas, P.W., Nicholas, J.S., Randall, P.K., Mardikian, P.N., Malcolm, R.J.,
2013. A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of co-
caine dependence. Am. J. Addict. 22, 443–452.
Lattal, K.M., Wood, M.A., 2013. Epigenetics and persistent memory: implications for recon-
solidation and silent extinction beyond the zero. Nat. Neurosci. 16, 124–129.
LeBlanc, K.H., Ostlund, S.B., Maidment, N.T., 2012. Pavlovian-to-instrumental transfer in
cocaine seeking rats. Behav. Neurosci. 126, 681–689.
LeBlanc, K.H., Maidment, N.T., Ostlund, S.B., 2013. Repeated cocaine exposure facilitates
the expression of incentive motivation and induces habitual control in rats. PLoS One
8, e61355.
References 109
LeBlanc, K.H., Maidment, N.T., Ostlund, S.B., 2014. Impact of repeated intravenous cocaine
administration on incentive motivation depends on mode of drug delivery. Addict. Biol.
19, 965–971.
Lee, J.L.C., 2008. Memory reconsolidation mediates the strengthening of memories by addi-
tional learning. Nat. Neurosci. 11, 1264–1266.
Lee, J.L.C., 2009. Reconsolidation: maintaining memory relevance. Trends Neurosci.
32, 413–420.
Lee, J.L.C., Milton, A.L., Everitt, B.J., 2006. Reconsolidation and extinction of conditioned
fear: inhibition and potentiation. J. Neurosci. 26, 10051–10056.
Lin, J., Liu, L., Wen, Q., Zheng, C., Gao, Y., Peng, S., Tan, Y., Li, Y., 2014. Rapamycin pre-
vents drug seeking via disrupting reconsolidation of reward memory in rats. Int. J. Neu-
ropsychopharmacol. 17, 127–136.
Liu, X., Palmatier, M.I., Caggiula, A.R., Donny, E.C., Sved, A.F., 2007. Reinforcement en-
hancing effect of nicotine and its attenuation by nicotinic antagonists in rats. Psychophar-
macology (Berl.) 194, 463–473.
Lofwall, M.R., Nuzzo, P.A., Campbell, C., Walsh, S.L., 2014. Aripiprazole effects on self-
administration and pharmacodynamics of intravenous cocaine and cigarette smoking in
humans. Exp. Clin. Psychopharmacol. 22, 238–247.
Lubin, F.D., Gupta, S., Parrish, R.R., Grissom, N.M., Davis, R.L., 2011. Epigenetic mecha-
nisms: critical contributors to long-term memory formation. Neuroscientist 17, 616–632.
Mac Callum, P.E., Hebert, M., Adamec, R.E., Blundell, J., 2013. Systemic inhibition of mTOR
kinase via rapamycin disrupts consolidation and reconsolidation of auditory fear memory.
Neurobiol. Learn. Mem. 112, 176–185.
Malvaez, M., Sanchis-Segura, C., Vo, D., Lattal, K.M., Wood, M.A., 2010. Modulation of
chromatin modification facilitates extinction of cocaine-induced conditioned place pref-
erence. Biol. Psychiatry 67, 36–43.
Malvaez, M., McQuown, S.C., Rogge, G.A., Astarabadi, M., Jacques, V., Carreiro, S.,
Rusche, J.R., Wood, M.A., 2013. HDAC3-selective inhibitor enhances extinction of
cocaine-seeking behavior in a persistent manner. Proc. Natl. Acad. Sci. U. S. A.
110, 2647–2652.
Miles, F.J., Everitt, B.J., Dickinson, A., 2003. Oral cocaine seeking by rats: action or habit?
Behav. Neurosci. 117, 927–938.
Milton, A.L., Everitt, B.J., 2010. The psychological and neurochemical mechanisms of drug
memory reconsolidation: implications for the treatment of addiction. Eur. J. Neurosci.
31, 2308–2319.
Milton, A.L., Everitt, B.J., 2012. The persistence of maladaptive memory: addiction, drug
memories and anti-relapse treatments. Neurosci. Biobehav. Rev. 36, 1119–1139.
Milton, A.L., Lee, J.L.C., Everitt, B.J., 2008. Reconsolidation of appetitive memories for both
natural and drug reinforcement is dependent on {beta}-adrenergic receptors. Learn. Mem.
15, 88–92.
Mousavi, S.G., Sharbafchi, M.R., Salehi, M., Peykanpour, M., Karimian Sichani, N.,
Maracy, M., 2015. The efficacy of N-acetylcysteine in the treatment of methamphetamine
dependence: a double-blind controlled, crossover study. Arch. Iran. Med. 18, 28–33.
Murray, J.E., Dilleen, R., Pelloux, Y., Economidou, D., Dalley, J.W., Belin, D., Everitt, B.J.,
2014. Increased impulsivity retards the transition to dorsolateral striatal dopamine control
of cocaine seeking. Biol. Psychiatry 76, 15–22.
Myers, K.M., Carlezon, W.A., 2012. D-cycloserine effects on extinction of conditioned re-
sponses to drug-related cues. Biol. Psychiatry 71, 947–955.
Nader, K., Schafe, G.E., LeDoux, J.E., 2000. The labile nature of consolidation theory. Nat.
Rev. Neurosci. 1, 216–219.
Nelson, A., Killcross, S., 2006. Amphetamine exposure enhances habit formation. J. Neurosci.
26, 3805–3812.
Nelson, A.J.D., Killcross, S., 2013. Accelerated habit formation following amphetamine ex-
posure is reversed by D1, but enhanced by D2, receptor antagonists. Front. Neurosci. 7, 76.
Nestler, E.J., 2013. Cellular basis of memory for addiction. Dialogues Clin. Neurosci.
15, 431–443.
Nic Dhonnchadha, B.A., Szalay, J.J., Achat-Mendes, C., Platt, D.M., Otto, M.W.,
Spealman, R.D., Kantak, K.M., 2010. D-cycloserine deters reacquisition of cocaine self-
administration by augmenting extinction learning. Neuropsychopharmacology
35, 357–367.
Nordquist, R.E., Voorn, P., de Mooij-van Malsen, J.G., Joosten, R.N.J.M.A., Pennartz, C.M.
A., Vanderschuren, L.J.M.J., 2007. Augmented reinforcer value and accelerated habit
formation after repeated amphetamine treatment. Eur. Neuropsychopharmacol.
17, 532–540.
O’Brien, C.P., Childress, A.R., McLellan, A.T., Ehrman, R., 1993. Developing treatments that
address classical conditioning. NIDA Res. Monogr. 135, 71–91.
O’Tousa, D., Grahame, N., 2014. Habit formation: implications for alcoholism research.
Alcohol 48, 327–335.
Olausson, P., Jentsch, J.D., Taylor, J.R., 2003. Repeated nicotine exposure enhances reward-
related learning in the rat. Neuropsychopharmacology 28, 1264–1271.
Olausson, P., Jentsch, J.D., Taylor, J.R., 2004a. Repeated nicotine exposure enhances respond-
ing with conditioned reinforcement. Psychopharmacology (Berl.) 173, 98–104.
Olausson, P., Jentsch, J.D., Taylor, J.R., 2004b. Nicotine enhances responding with condi-
tioned reinforcement. Psychopharmacology (Berl.) 171, 173–178.
Olmstead, M.C., Lafond, M.V., Everitt, B.J., Dickinson, A., 2001. Cocaine seeking by rats is a
goal-directed action. Behav. Neurosci. 115, 394–402.
Ostlund, S.B., Maidment, N.T., Balleine, B.W., 2010. Alcohol-paired contextual cues produce
an immediate and selective loss of goal-directed action in rats. Front. Integr. Neurosci.
4, 19.
Ostlund, S.B., LeBlanc, K.H., Kosheleff, A.R., Wassum, K.M., Maidment, N.T., 2014. Phasic
mesolimbic dopamine signaling encodes the facilitation of incentive motivation produced
by repeated cocaine exposure. Neuropsychopharmacology 39, 2441–2449.
Palmatier, M.I., Liu, X., Caggiula, A.R., Donny, E.C., Sved, A.F., 2007. The role of nicotinic
acetylcholine receptors in the primary reinforcing and reinforcement-enhancing effects of
nicotine. Neuropsychopharmacology 32, 1098–1108.
Paolone, G., Botreau, F., Stewart, J., 2009. The facilitative effects of D-cycloserine on extinc-
tion of a cocaine-induced conditioned place preference can be long lasting and resistant to
reinstatement. Psychopharmacology (Berl.) 202, 403–409.
Parvaz, M.A., Konova, A.B., Proudfit, G.H., Dunning, J.P., Malaker, P., Moeller, S.J.,
Maloney, T., Alia-Klein, N., Goldstein, R.Z., 2015. Impaired neural response to negative
prediction errors in cocaine addiction. J. Neurosci. 35, 1872–1879.
Peters, J., Kalivas, P.W., Quirk, G.J., 2009. Extinction circuits for fear and addiction overlap in
prefrontal cortex. Learn. Mem. 16, 279–288.
Price, K.L., Baker, N.L., McRae-Clark, A.L., Saladin, M.E., Desantis, S.M., Santa Ana, E.J.,
Brady, K.T., 2012. A randomized, placebo-controlled laboratory study of the effects of
References 111
D-cycloserine on craving in cocaine-dependent individuals. Psychopharmacology (Berl.)

226 (4), 739–746.
Quinn, J.J., Hitchcott, P.K., Umeda, E.A., Arnold, A.P., Taylor, J.R., 2007. Sex chromosome
complement regulates habit formation. Nat. Neurosci. 10, 1398–1400.
Quirk, G.J., Mueller, D., 2008. Neural mechanisms of extinction learning and retrieval.
Raybuck, J.D., Lattal, K.M., 2014. Differential effects of dorsal hippocampal inactivation on
expression of recent and remote drug and fear memory. Neurosci. Lett. 569, 1–5.
Raybuck, J.D., McCleery, E.J., Cunningham, C.L., Wood, M.A., Lattal, K.M., 2013. The his-
tone deacetylase inhibitor sodium butyrate modulates acquisition and extinction of
cocaine-induced conditioned place preference. Pharmacol. Biochem. Behav.
106, 109–116.
Ressler, K.J., Rothbaum, B.O., Tannenbaum, L., Anderson, P., Graap, K., Zimand, E.,
Hodges, L., Davis, M., 2004. Cognitive enhancers as adjuncts to psychotherapy: use of
D-cycloserine in phobic individuals to facilitate extinction of fear. Arch. Gen. Psychiatry
61, 1136–1144.
Robbins, T.W., Everitt, B.J., 1999. Drug addiction: bad habits add up. Nature 398, 567–570.
Robinson, M.J.F., Franklin, K.B.J., 2010. Reconsolidation of a morphine place preference:
impact of the strength and age of memory on disruption by propranolol and midazolam.
Behav. Brain Res. 213, 201–207.
Robinson, M.J.F., Armson, M., Franklin, K.B.J., 2011. The effect of propranolol and midazo-
lam on the reconsolidation of a morphine place preference in chronically treated rats.
Front. Behav. Neurosci. 5, 42.
Root, D.H., Fabbricatore, A.T., Barker, D.J., Ma, S., Pawlak, A.P., West, M.O., 2009. Evi-
dence for habitual and goal-directed behavior following devaluation of cocaine: a multi-
faceted interpretation of relapse. PLoS One 4 (9), e7170.
Saladin, M.E., Gray, K.M., McRae-Clark, A.L., Larowe, S.D., Yeatts, S.D., Baker, N.L.,
Hartwell, K.J., Brady, K.T., 2013. A double blind, placebo-controlled study of the effects
of post-retrieval propranolol on reconsolidation of memory for craving and cue reactivity
in cocaine dependent humans. Psychopharmacology (Berl.) 226, 721–737.
Sanchez, H., Quinn, J.J., Torregrossa, M.M., Taylor, J.R., 2010. Reconsolidation of a cocaine-
associated stimulus requires amygdalar protein kinase A. J. Neurosci. 30, 4401–4407.
Santa Ana, E.J., Rounsaville, B.J., Frankforter, T.L., Nich, C., Babuscio, T., Poling, J.,
Gonsai, K., Hill, K.P., Carroll, K.M., 2009. D-Cycloserine attenuates reactivity to smoking
cues in nicotine dependent smokers: a pilot investigation. Drug Alcohol Depend.
104, 220–227.
Sara, S.J., 2000. Retrieval and reconsolidation: toward a neurobiology of remembering. Learn.
Mem. 7, 73–84.
Schwabe, L., Wolf, O.T., 2009. Stress prompts habit behavior in humans. J. Neurosci.
29, 7191–7198.
Schwabe, L., Wolf, O.T., 2010. Socially evaluated cold pressor stress after instrumental learn-
ing favors habits over goal-directed action. Psychoneuroendocrinology 35, 977–986.
Schwabe, L., Tegenthoff, M., H€offken, O., Wolf, O.T., 2010. Concurrent glucocorticoid and
noradrenergic activity shifts instrumental behavior from goal-directed to habitual control.
J. Neurosci. 30, 8190–8196.
See, R.E., Waters, R.P., 2010. Pharmacologically-induced stress: a cross-species probe for
translational research in drug addiction and relapse. Am. J. Transl. Res. 3, 81–89.
Serlin, H., Torregrossa, M.M., 2014. Adolescent rats are resistant to forming ethanol seeking
habits. Dev. Cogn. Neurosci. http://dx.doi.org/10.1016/j.dcn.2014.12.002
Sevenster, D., Beckers, T., Kindt, M., 2013. Prediction error governs pharmacologically in-
duced amnesia for learned fear. Science 339, 830–833.
Shi, X., Miller, J.S., Harper, L.J., Poole, R.L., Gould, T.J., Unterwald, E.M., 2014. Reactiva-
tion of cocaine reward memory engages the Akt/GSK3/mTOR signaling pathway and can
be disrupted by GSK3 inhibition. Psychopharmacology (Berl.) 231 (16), 3109–3118.
Shiflett, M.W., 2012. The effects of amphetamine exposure on outcome-selective Pavlovian-
instrumental transfer in rats. Psychopharmacology (Berl.) 223, 361–370.
Sinha, R., Shaham, Y., Heilig, M., 2011. Translational and reverse translational research on the
role of stress in drug craving and relapse. Psychopharmacology (Berl.) 218, 69–82.
Soeter, M., Kindt, M., 2011. Disrupting reconsolidation: pharmacological and behavioral ma-
nipulations. Learn. Mem. 18, 357–366.
Sorg, B.A., 2012. Reconsolidation of drug memories. Neurosci. Biobehav. Rev.
36, 1400–1417.
Taylor, J.R., Horger, B.A., 1999. Enhanced responding for conditioned reward produced by
intra-accumbens amphetamine is potentiated after cocaine sensitization. Psychopharma-
cology (Berl.) 142, 31–40.
Taylor, J.R., Jentsch, J.D., 2001. Repeated intermittent administration of psychomotor
stimulant drugs alters the acquisition of Pavlovian approach behavior in rats: differential
effects of cocaine, D-amphetamine and 3,4-methylenedioxymethamphetamine
(“Ecstasy”). Biol. Psychiatry 50, 137–143.
Taylor, J.R., Olausson, P., Quinn, J.J., Torregrossa, M.M., 2009. Targeting extinction and
reconsolidation mechanisms to combat the impact of drug cues on addiction.
Neuropharmacology 56 (Suppl. 1), 186–195.
Thanos, P.K., Bermeo, C., Wang, G.-J., Volkow, N.D., 2009. D-cycloserine accelerates the
extinction of cocaine-induced conditioned place preference in C57bL/c mice. Behav.
Brain Res. 199, 345–349.
Thanos, P.K., Bermeo, C., Wang, G.-J., Volkow, N.D., 2011. D-cycloserine facilitates extinc-
tion of cocaine self-administration in rats. Synapse 65, 938–944.
Torregrossa, M.M., Taylor, J.R., 2012. Learning to forget: manipulating extinction and recon-
solidation processes to treat addiction. Psychopharmacology (Berl.).
Torregrossa, M.M., Sanchez, H., Taylor, J.R., 2010. D-cycloserine reduces the context spec-
ificity of pavlovian extinction of cocaine cues through actions in the nucleus accumbens.
J. Neurosci. 30, 10526–10533.
Torregrossa, M.M., Corlett, P.R., Taylor, J.R., 2011. Aberrant learning and memory in addic-
tion. Neurobiol. Learn. Mem. 96 (4), 609–623.
Torregrossa, M.M., Gordon, J., Taylor, J.R., 2013. Double dissociation between the anterior
cingulate cortex and nucleus accumbens core in encoding the context versus the content of
pavlovian cocaine cue extinction. J. Neurosci. 33, 8370–8377.
Tronson, N.C., Taylor, J.R., 2007. Molecular mechanisms of memory reconsolidation. Nat.
Rev. Neurosci. 8, 262–275.
Tronson, N.C., Taylor, J.R., 2013. Addiction: a drug-induced disorder of memory reconsoli-
dation. Curr. Opin. Neurobiol. 23, 573–580.
Tronson, N.C., Wiseman, S.L., Olausson, P., Taylor, J.R., 2006. Bidirectional behavioral plas-
ticity of memory reconsolidation depends on amygdalar protein kinase A. Nat. Neurosci.
9, 167–169.
References 113
Wan, X., Torregrossa, M.M., Sanchez, H., Nairn, A.C., Taylor, J.R., 2014. Activation of ex-
change protein activated by cAMP in the rat basolateral amygdala impairs reconsolidation
of a memory associated with self-administered cocaine. PLoS One 9, e107359.
Watson, B.J., Wilson, S., Griffin, L., Kalk, N.J., Taylor, L.G., Munafò, M.R., Lingford-
Hughes, A.R., Nutt, D.J., 2011. A pilot study of the effectiveness of D-cycloserine during
cue-exposure therapy in abstinent alcohol-dependent subjects. Psychopharmacology
(Berl.) 216, 121–129.
Wyvell, C.L., Berridge, K.C., 2001. Incentive sensitization by previous amphetamine expo-
sure: increased cue-triggered “wanting” for sucrose reward. J. Neurosci. 21, 7831–7840.
Yamada, D., Zushida, K., Wada, K., Sekiguchi, M., 2009. Pharmacological discrimination of
extinction and reconsolidation of contextual fear memory by a potentiator of AMPA re-
ceptors. Neuropsychopharmacology 34, 2574–2584.
Yin, H.H., Knowlton, B.J., 2006. The role of the basal ganglia in habit formation. Nat. Rev.
Neurosci. 7, 464–476.
Yin, H.H., Knowlton, B.J., Balleine, B.W., 2006. Inactivation of dorsolateral striatum en-
hances sensitivity to changes in the action-outcome contingency in instrumental condition-
ing. Behav. Brain Res. 166, 189–196.
Zapata, A., Minney, V.L., Shippenberg, T.S., 2010. Shift from goal-directed to habitual co-
caine seeking after prolonged experience in rats. J. Neurosci. 30, 15457–15463.
Zhou, W., Kalivas, P.W., 2008. N-acetylcysteine reduces extinction responding and induces
enduring reductions in cue- and heroin-induced drug-seeking. Biol. Psychiatry
63, 338–340.
CHAPTER
Neuroscience of drug
craving for addiction
medicine: From circuits to
therapies
7
Hamed Ekhtiari*,†,{,1, Padideh Nasseri*,†, Fatemeh Yavari*, Azarkhsh Mokri§,
John Monterosso¶,jj,#
*Neurocognitive Laboratory, Iranian National Center for Addiction Studies (INCAS), Tehran
University of Medical Sciences, Tehran, Iran
†
Translational Neuroscience Program, Institute for Cognitive Science Studies (ICSS), Tehran, Iran
{
Research Center for Molecular and Cellular Imaging (RCMCI), Tehran University of Medical
§
Clinical Department, Iranian National Center for Addiction Studies (INCAS), Tehran University
of Medical Sciences, Tehran, Iran
¶
Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA
jj
Department of Psychology, University of Southern California, Los Angeles, CA, USA
#
Brain and Creativity Institute, University of Southern California, Los Angeles, CA, USA
1
Corresponding author: Tel.: +98-912-1885898; Fax: +98-21-55412232
Abstract
Drug craving is a dynamic neurocognitive emotional–motivational response to a wide range of
cues, from internal to external environments and from drug-related to stressful or affective
events. The subjective feeling of craving, as an appetitive or compulsive state, could be con-
sidered a part of this multidimensional process, with modules in different levels of conscious-
ness and embodiment. The neural correspondence of this dynamic and complex phenomenon
may be productively investigated in relation to regional, small-scale networks, large-scale net-
works, and brain states. Within cognitive neuroscience, this approach has provided a long list
of neural and cognitive targets for craving modulations with different cognitive, electrical, or
pharmacological interventions. There are new opportunities to integrate different approaches
for carving management from environmental, behavioral, psychosocial, cognitive, and neural
perspectives. By using cognitive neuroscience models that treat drug craving as a dynamic and
multidimensional process, these approaches may yield more effective interventions for addic-
tion medicine.

115
116 CHAPTER 7 Neuroscience of drug craving for addiction medicine
Keywords
Substance use disorders, Drug craving, Functional magnetic resonance imaging, Neurocogni-
tive, Integrative model, Addiction medicine
1 INTRODUCTION
Substance use disorder as a brain disease is characterized by persistent drug-
seeking and drug-taking behaviors despite significant negative consequences in
physical, emotional, social, and occupational aspects of the individual’s life
(Shariatirad et al., 2013; Volkow et al., 2011). Drug craving is considered by many
researchers to be one of the main driving forces of drug-taking behaviors (Anton,
1999; Kassel and Shiffman, 1992; Robinson and Berridge, 1993). In spite of grow-
ing interest in craving which led to its consideration as one of the criteria for sub-
stance use disorders in DSM-5, there is a lack of consensuses about its definition
(Sayette et al., 2000) and underlying causes (Drummond, 2001). This controversy
may arise from insufficient understanding of the phenomenon. Common psycho-
logical perspectives describe craving as a subjective motivational state in which
an individual experiences an intense urge to engage in a behavior (here drug use),
especially when that behavior is not in accord with longer range interests and
goals. However, while the subjective state of wanting is important in most concep-
tions of craving, modern theorists have argued that it is only one component of
craving. The complete mental entanglement of craving can include a variety of
related phenomena such as memories (specific episodes of past use), positive ex-
pectancies, difficulties in concentration (on things other than the target of the
craving), heightened attention to substance-related stimuli, particular interpreta-
tions of physiological reactions that can occur in response to substance cues, and
actual automatic behavior associated with substance use (Maarefvand et al., 2013;
Tiffany, 1990).
The ambiguity of craving is not limited to its definition. Different interventions
such as mindfulness relapse prevention (Witkiewitz et al., 2005), attentional
bias modification (Cox et al., 2014; Field et al., 2014), pharmacological treat-
ments (Dackis et al., 2005; Johansson et al., 2006), and non-invasive brain
stimulation (NIBS) (Gorelick et al., 2014; Shahbabaie et al., 2014) designed to
manage craving and subsequently prevent relapse, target only some aspects of
drug craving. Moreover, there is little evidence regarding interactions between
these interventions and particular aspects of drug craving. Identification of these
interactions could point a way forward by suggesting complimentary interventions
that address distinct components of craving (a difficult task in real-life addiction
medicine settings).
In recent years, the methods of cognitive neuroscience are increasingly being used
to study cognitive processes underlying different psychiatric disorders including
2 Models of drug craving: From behavioral to cognitive perspectives 117
substance use disorders. Neuroimaging techniques, such as functional magnetic reso-

nance imaging (fMRI) and positron emission tomography, have been widely used to
identify neural correlates of craving (Ekhtiari et al., 2008; Tabatabaei-Jafari et al.,
2014). This naturally raises the question, “Do the advances of neuroscience provide
a bases from which to update existing models of drug craving, and to develop more
effective neurocognitive treatments for addiction medicine?” (Ekhtiari, 2010).
2 MODELS OF DRUG CRAVING: FROM BEHAVIORAL TO

COGNITIVE PERSPECTIVES
Investigators from different perspectives have advanced conceptual accounts of the
nature of craving and its associated conditions, as well as its underlying causes. Most
of the models can be divided into two main categories: conditioning theories and
cognitive theories (Singleton and Gorelick, 1998). Conditioning theories consider
craving to be Pavlovian responses that occur as a result of continuous pairings of
the effects of a psychoactive substance in the brain with presented environmental
cues. These conditioned responses can result from repeated pairing of stimuli with
positive effects of substance use (appetitive, substance-like models) (Stewart et al.,
1984), or the alleviation of negative effects of withdrawal (compulsive, withdrawal-
like models) (Ludwig et al., 1974; Siegel, 1989), or can happen because of incentive
motivational features of a substance that sensitize the brain and subsequently change
the perception of cues and make the substance wanted (incentive-sensitization
model) (Robinson and Berridge, 1993).
In contrast, cognitive theories are based on the assumption that responses to
substance-related cues involve various cognitive processes. According to these the-
ories, craving either is mediated by beliefs and expectations about the positive effects
of substance use, such as pleasure, relaxation, or relief from negative effects of with-
drawal (cognitive – behavioral model) (Larimer et al., 1999), or considered as an
automatic cognitive processes elicited when substance use is impeded (cognitive
model of drug urges and drug use behavior) (Tiffany, 1990).
Conditioning theories have been influential in the development of cue-exposure
treatments, while cognitive theories have been the basis for other cognitive therapies
of substance use disorders (Drummond, 2001).
Although all these models have tried to explain the nature of craving, none of
them provide a complete explanation of the multidimensional phenomenon of crav-
ing. In recent years, neuroscience has identified associations between craving and
brain regions, networks, and cognitive functions. Building on these findings, an
extended explanation can be provided which takes into account varied components
of craving and links neural mechanisms to cognitive and behavioral functions and
environmental factors.
3 NEUROCOGNITIVE BASIS OF DRUG CRAVING: REGION-

BASED PERSPECTIVE
In recent years, advances in neuroscience methodologies, and particularly in brain-
imaging techniques, have allowed better understanding of drug craving by linking
the processes involved in craving to certain brain pathways. There are about 200
functional neuroimaging studies, mainly fMRI, which investigated craving with
cue-reactivity paradigms among different populations with substance use disorders.
Cue-reactivity paradigms generally involve exposure of substance or stress/
emotional-related cues in block or event design during image acquisitions.
As it has been shown in Table 1, drug craving could be considered a multidimen-
sional phenomenon associated with a range of neurocognitive functions. The main
cognitive processes elicited during cue exposure can be categorized into six different
domains spreading from bottom-up perceptual processes to top-down regulatory
executive ones (Table 1). These processes involve a wide range of activities in
different subcortical and cortical regions and can be activated in different levels
based on various individualized factors such as severity and longevity of the disorder
and current status of drug use (e.g., recreational user, active user, treatment seeker or
abstinent) (Jasinska et al., 2014).
4 NEUROCOGNITIVE BASIS OF DRUG CRAVING:

NETWORK-BASED PERSPECTIVE
It has been shown that many cognitive functions result from the coordinated activa-
tions of different brain regions as a network, and therefore many neurological and
psychiatric diseases likely reflect abnormality in brain networks (Fox et al., 2012;
Lerman et al., 2014). Therefore, in order to better understand the neurocognitive ba-
sis of substance use disorder (and particularly of drug craving), we need to consider
links between craving phenomena and brain network activity. From a networks per-
spective, the integrity of network interactions and disrupted functional connectivity
between them can provide us with clues about the neurocognitive dysfunctions of
addiction, and potential targets for effective interventions.
There are various functional brain networks suggested to be involved in different
cognitive functions. Six well-known brain networks could explain the main cognitive
functions involved in the cue reactivity among drug users as follows (DeWitt et al.,
2015; Janes et al., 2015; Lerman et al., 2014; Potvin et al., 2015; Robbins et al., 2008;
Seo and Sinha, 2014).
4.1 STRIATAL-LIMBIC NETWORK

A common characteristic of most substance of abuse is their ability to increase extra-
cellular dopamine concentration in ventral striatum, amygdala, hypothalamus, and
orbitofrontal cortex which are innervated by dopaminergic projections from the ventral
Table 1 Cognitive Dimensions and Functions Associated with Cue-Elicited Drug Craving and Their Corresponding Brain Areas
Among People with Substance Use Disorders Based on Imaging Studies Using Cue-Reactivity Paradigms
Domain Subdomains Possible Related Regions Possible Relations to Cue Reactivity
Perception Sensory processing Middle occipital gyrus (Charboneau et al., 2013; Chase Enhanced activity in visual cortex is consistently
and perception et al., 2011), lingual gyrus (Engelmann et al., 2012; Park observed in studies using visual cues. Given top-down
et al., 2007), cuneus (Charboneau et al., 2013) influences over visual processing and evidence that
higher value targets recruit greater visual activation, it is
likely that cue value mediates this effect.
Object recognition Inferior temporal cortex (Park et al., 2007), fusiform gyrus The users probably acquire an object recognition and
and classification (Due et al., 2002) classification expertise for cues associated with their
substance of abuse. This expertise helps them to have
an efficient access to the semantic knowledge, which
may in turn enhance processing of substance cues.
Sensory imagery Primary and secondary sensory cortices (Kilts et al., 2001) Imagery carries the emotional qualities of the desired
event and also mimics expected pleasure or relief.
Continual elaboration of the imagery can elicit craving
and trigger mechanisms of substance use.
Interoception Insular cortex (Goudriaan et al., 2010) Interoceptive processes lead to perception of cue-
evoked conditioned feeling states, providing the
subjective feeling of drug craving.
Action and Motor preparation Primary motor cortex (Smolka et al., 2006), premotor Drug cues cause motor cortex activity, because the
motor and imagery cortex (Smolka et al., 2006), supplementary motor area resulting action is habitually overlearned. Also,
functions (Smolka et al., 2006), precuneus (Engelmann et al., 2012) anticipation can act as a conditioned stimulus triggering
motor mechanisms related to drug administration.
Motor planning Inferior parietal lobule (Garavan et al., 2000), superior Motor planning mechanisms link perception and action
parietal lobule (Garavan et al., 2000), posterior middle by integrating sensory and motor signals which are the
temporal gyrus (Yalachkov et al., 2009), inferior temporal processing of spatial representations for reaching and
cortex (Yalachkov et al., 2009) grasping of drug-related objects and sensory guidance
of movements.
Motor initiation and Dorsal striatum (McClernon et al., 2009), primary motor Regular exposure to drug-related cues can help the
execution cortex (McClernon et al., 2009) development of automatized actions related to initiation
and execution of consuming drugs. These actions can
raise the probability of performing drug-taking actions
when addicts view drug-related cues.
Habitual responses Dorsal striatum (Volkow et al., 2006), cerebellum (Wang Habitual response can be operationalized, as stimulus–
et al., 2013) response links (often contrasted with response–
outcome links that serve value-based action) are
important in compulsive drug seeking and drug taking.
Continued
Table 1 Cognitive Dimensions and Functions Associated with Cue-Elicited Drug Craving and Their Corresponding Brain Areas
Among People with Substance Use Disorders Based on Imaging Studies Using Cue-Reactivity Paradigms—cont’d
Domain Subdomains Possible Related Regions Possible Relations to Cue Reactivity
Learning Emotional memory Amygdala (Grant et al., 1996), hippocampus (Lou et al., Drug-related cues can trigger retrieving of drug-
and retrieval 2012) associated memories and their affective/motivational
memory value. This increases the degree of vulnerability of drug
users to relapse.
Procedural memory Cerebellum (Wang et al., 1999), dorsal striatum (Volkow Procedural memories can contribute to learning and
retrieval et al., 2006) formation of drug use behavior, which in turn will be
triggered by drug-related cues.
Attention Sensory attention Lingual gyrus (Engelmann et al., 2012), fusiform gyrus Drug-related cues can have effects like rare targets on
(mainly visual) (Engelmann et al., 2012), precuneus (Engelmann et al., brain, which lead to activate brain systems important for
2012) highlighting relevant and meaningful stimuli in the
environment.
Attention shifting Superior temporal gyrus (Luijten et al., 2011), superior Because of an enhanced early processing of drug cues,
(bias) parietal cortex (Luijten et al., 2011), anterior cingulate the sensory representations of drug-related cues
cortex (Luijten et al., 2011) activate and trigger robust attentional biases in drug
users. These biases can lead to decision-making and
motor responses that increase the chance of
drug-seeking behavior.
Executive Goal setting, error Anterior cingulate cortex (Goldstein et al., 2007) Substance users, as a group, exhibit deficits in the goal-
cognitive detection, and based attentional control, which includes checking error
control monitoring behaviors (conflicts) and correcting actions. Goal-setting
processes and error detection and monitoring are
activated during cue exposure. Disrupted processing
can result in impulsive behaviors that lead to drug-taking
behaviors.
Execution of goal- Orbitofrontal cortex (Bonson et al., 2002), dorsolateral By integrating sensory inputs that are triggered by drug-
directed behavior prefrontal cortex (McBride et al., 2006) related cues, reward expectation and motivation, and
homeostatic signals about the current state and needs of
the person, the behavior for obtaining desired outcomes
will be selected and executed.
Self-referential Anterior cingulate cortex (Moeller et al., 2014), posterior Substance users have deficits in appraising the
processing cingulate cortex (Mel’nikov et al., 2014), precuneus motivational significance of errors and self-referential
(Mel’nikov et al., 2014) processing. This may reduce concern about negative
outcomes of behaviors, which can in turn lead them to
greater drug use.
Response inhibition Inferior frontal gyrus (Prisciandaro et al., 2014) Individuals with substance use disorders sometimes try
to inhibit their cravings when confronted with drug-
related cues.
Emotion Emotion generation Amygdala (Courtney et al., 2015), limbic system (Courtney Drug-related cues in environment are recognized as
et al., 2015) immediate sources of pleasure and reward and increase
the arousal of substance users, and produce intense
positive and or negative emotions related to the
appetitive/aversive nature of craving.
Emotion regulation Anterior cingulate cortex (Goldstein et al., 2007), inferior Substance abusers try to control their emotions elicited
frontal gyrus (Goldstein et al., 2007), medial orbitofrontal by exposure to drug cues or internal/external stressors.
cortex (Goldstein et al., 2007)
Motivation Prediction and Orbitofrontal cortex (Goldstein et al., 2007), dorsolateral The anticipation of receiving rewards and expectation of
anticipation of prefrontal cortex (Müller-Oehring et al., 2013), posterior availability of drug in the immediate future can be
reward and cingulate cortex (Müller-Oehring et al., 2013) activated in cue exposure and contribute to feelings of
punishment craving.
Appetitive Ventral striatum (David et al., 2007), amygdala (Brody Appetitive motivation toward drugs is created by
motivation et al., 2002), orbitofrontal cortex (Brody et al., 2002) classical conditioning. Through associative (classical)
conditioning, abusers recognize drug cues as pleasant
stimuli. This enhanced motivation encourages addicts to
procure drugs and results in craving sensations and
drug-seeking responses.
tegmental area (Hyman et al., 2006). This circuit originally responds to natural rewards
such as food or sex, but drugs of abuse can also activate reward processing in these
regions, establish reward-related memories, and promote the actions leading to the
reward (Everitt and Robbins, 2005). Also, it has been demonstrated that most midbrain
dopaminergic neurons show phasic firing following conditioned visual, auditory, and
somatosensory reward-predicting stimuli (Schultz, 2007) and the activity of the neu-
rons is briefly depressed by stimuli predicting the explicit absence of reward. There-
fore, the activity of this network in the presence of substance-related cues is in
accordance with classical conditioning theories of addiction. Activity within this
network triggers a pattern of physiological (e.g., increase in heart rate) and cognitive
(e.g., increase in attention) reactions, which can lead to drug seeking and taking.
4.2 SALIENCE NETWORK

The brain receives a continuous flow of exogenous and endogenous information.
Success in performing tasks which are beneficial for the individual’s survival and
well-being depends on the capacity to identify which stimuli merit the very limited
resources associated with attention. “Salience” refers to the outcome of this identi-
fication process (and is therefore intimately connected with attention, see below).
Increased prefrontal norepinephrine outflow has been reported in response to both
rewarding and aversive unconditioned stimuli with high motivational salience in an-
imals (Sara and Segal, 1991). In humans, the salience network (SN), which includes
the anterior cingulate cortex (ACC) and insula, has been suggested to play a critical
role in assessing the relevance of internal and external stimuli and integrating this
information to guide behavior (Seeley et al., 2007).
ACC has been shown to be activated by salient stimuli including reward-related
stimuli and also stimuli that elicit pain or negative affect (Shackman et al., 2011).
Furthermore, the insula integrates information from several sensory modalities
and is important for translating emotionally salient stimuli information into a guide-
line for goal-directed behavior (Cloutman et al., 2012).
In regard to drug dependence, drug-related cues and the internal states that are
generated by emotional/stressful cues tend to be experienced as highly salient
“internal and external stimuli,” as evidenced by the activity within the SN (Janes
et al., 2015). It has been shown that greater insula–ACC coupling at rest was signif-
icantly correlated with enhanced smoking cue reactivity in brain areas associated
with attention and motor preparation, including the visual cortex, right ventral lateral
prefrontal cortex, and the dorsal striatum (Janes et al., 2015). Moreover, a triple
network connectivity of SN with executive control network (ECN) and default mode
network (DMN) has been proposed, suggesting the role of SN in switching activity
between DMN and ECN based on attribution of saliency to internal or external stim-
uli (Menon, 2011). It has been suggested that in substance use disorders, the activity
of SN leads to allocation of attentional resources toward drug craving and thereupon
to a bias toward enhanced DMN activity and decreased ECN operations (Sutherland
et al., 2012).
4 Neurocognitive basis of drug craving: Network-based perspective 123
4.3 ATTENTION NETWORK

It has been shown that goal pursuit makes individual more sensitive to goal-related
cues and thus those cues get higher priority in cognitive processing, which entails
attentional bias (Hoelscher et al., 1981). In the case of substance use, there are biases
in attentional processing of substance-related stimuli because of their incentive
salience; hence, they can grab substance abusers’ attention. The extent of attentional
bias has been proposed to be highly correlated with the intensity of the subjective
feeling of craving and with the risk of relapse (Field and Cox, 2008).
From two neuronal networks that are thought to be specifically associated with
attentional processing, the ventral and the dorsal attention networks, the dorsal atten-
tional network (DAN) including regions of the dorsal and lateral frontal cortices, and
superior parietal lobule (Corbetta and Shulman, 2002) have been shown to be over-
active during drug cue exposure (Luijten et al., 2011). Neurophysiological studies
indicate that in addition to being recruited for top-down selection (Westerberg
et al., 2011), the DAN is modulated by the bottom-up distinctiveness of objects in
a visual scene (Corbetta and Shulman, 2002). Thus, the aforementioned hyperactiv-
ity during cue exposure could be the result of increased effort for top-down
regulation of attentional bias (Lubman et al., 2004). The hyperactivity of DAN which
seems to be functionally connected to regions of ECN (Dosenbach et al., 2007)
makes use of limited available attentional resources and subsequently interferes
with day-to-day life or employment of abstinence-oriented coping skills (Waters
et al., 2003).
4.4 DEFAULT MODE NETWORK

The DMN is a set of brain regions that exhibits strong low-frequency oscillations
coherent during resting state and is thought to be activated when individuals are
focused on their internal mental-state processes, such as self-referential processing,
interoception, autobiographical memory retrieval, or imagining future. DMN is
deactivated during cognitive task performance. The posterior cingulate cortex, pre-
cuneus, medial prefrontal, and inferior parietal cortices are thought to be parts of
DMN (Broyd et al., 2009).
Previous studies have suggested that DMN activation is positively correlated
with drug craving/withdrawal, while substance consumption suppresses activity of
DMN (Cole et al., 2010; Sutherland et al., 2012). Also, as it has been mentioned
earlier, DMN–SN–ECN coupling is disrupted in substance use disorders. Alterna-
tions in SN–DMN coupling appear to be related to drug craving, which may result
in difficulty in disengaging from self-centered thoughts associated with craving
(Lerman et al., 2014). Alternations in coupling between DMN–SN–ECN and more
specifically failure in suppressing the DMN activity can increase the error rates in
cognitive tasks (especially tasks involving inhibitory control) and can interfere with
goal-directed behaviors (Eichele et al., 2008). This can lead to higher vulnerability
of substance users to relapse in the presence of substance-related cues.
4.5 MEMORY NETWORKS

The level of stimuli’s influence on attentional and motivational processes can de-
termine how individuals acquire and encode those stimuli and related information.
Drugs can positively modulate and engage attentional and motivational systems of
the brain; hence, drug-related information including drug-taking behaviors and
drug-related cues are strongly encoded. The activation of memory systems of
the brain during cue-induced craving has been observed from the very first imag-
ing studies (Grant et al., 1996). Drug-related memories contribute to the saliency
processing of the cues and associated feelings of craving within a spectrum from
appetitive (liking) to compulsive (wanting) feelings. Studies shed light on the im-
portance of two types of memory networks in substance abuse: emotional and
procedural.
During the period of initial substance use, memories of substance use are formed
and become strong, and drug-taking behaviors are initiated with the goal of
experiencing the reinforcing effects of the drug. The amygdala and hippocampus
play a key role in the conditioned reinforcing effects of drugs of abuse. The amygdala
is involved in emotional processing of discrete cues, while the hippocampus has a
major role in processing contextual cues and spatial learning (Selden et al., 1991).
The interaction of the amygdala and hippocampus is implicated in the mediation
of attention toward cues that are highly related to the formation of drug use memories
(Floresco et al., 2001), which in return can induce craving for drug of choice.
By contrast, dorsal striatum and cerebellum have been assumed to mediate pro-
cedural learning and habit formation in addiction (Miquel et al., 2009; Robbins et al.,
2008). Habits are products of stimulus–response learning in which reinforcers pri-
marily strengthen the stimulus–response associations. Constant confrontation with
drug-related cues and regular drug consumption facilitate formation of habits and
automatized actions. These actions can be triggered by substance-related cues and
increase the chance of drug abuse in people with substance use disorders
(Yalachkov et al., 2010).
4.6 EXECUTIVE CONTROL NETWORK

The ability to have cognitive control over impulses is a key process in self-regulating
healthy behavior. An important characteristic of substance use disorder is an atten-
uated top-down inhibitory control and an augmented bottom-up signal of appetitive
salience for drugs (Bechara, 2005). The ECN includes the lateral prefrontal and
parietal cortices and is thought to be involved in goal-directed behavior and cognitive
control. The ECN has been shown to have abnormal activity in substance use disor-
ders (Krmpotich et al., 2013; Sutherland et al., 2012). As we mentioned earlier, the
decreased ECN activity combined with less suppression of DMN activity in cue-
exposure events has been observed in imaging studies. This reduction in ECN activ-
ity is reflected in difficulty in executing top-down cognitive control over subjective
feeling of craving, which can lead to drug consumption (Lerman et al., 2014).
5 Neurocognitive model of drug craving as a dynamic process 125
5 NEUROCOGNITIVE MODEL OF DRUG CRAVING AS A DYNAMIC

PROCESS
A schematic of drug craving processing pipeline, beginning from external or internal
input stimuli, and ending with drug-taking behavior or successful abstinence, is
shown in Fig. 1. As can be seen in the model, the pathway of drug-craving processing
is activated by the environmental stimuli (E), which stand in a spectrum from inter-
nal/external emotional/drug-related cues. These cues elicit distinct yet collaborative
bottom-up and top-down attentional processes that generate attentional allocation
(A) to drug-relevant cues (Field and Cox, 2008). The focused attention toward cues
and retrieval of previous substance abuse-related memories then triggers saliency
evaluation processes (S) (Janes et al., 2015). Sensitized brain circuits attribute path-
ologically high level of salience to drug-associated cues. This salience can be
implicit or explicit, i.e., in the form of “unconscious wanting” or “conscious craving”
(Robinson and Berridge, 2008). Saliency evaluation can result in subjective feeling
of craving (in a spectrum from positive appetitive to negative compulsive states)
which drives ECN to take action for execution of drug-taking behavior or successful
effortful executive control that leads to abstinence.
With development of substance use disorder over time, a transition could happen
from recreational to habitual use of drugs, i.e., immediate rewards from drug intake
with appetitive craving fade and drug-taking behaviors become more compulsive or
habitual (Potenza et al., 2012).
Other than the feed-forward connections in this model, there are also several feed-
back connections; for example, a reciprocal excitatory interaction has been suggested
between craving and substance-related attentional bias, i.e., increase in craving makes
substance-related stimuli more salient and increase in focused attention toward these
FIGURE 1
A multimodular neurocognitive model for drug craving as a dynamic process. Abbreviations:
E, environment (internal or external); A, attentional processing; S, salience processing;
SC, subjective craving; EC, executive control; R, response.
cues leads to more boosting of craving (Franken, 2003). Another feedback connection is
related to when drug use (e.g., first sips) acts as a multidimensional drug-related cue; in
this way, the pathway in Fig. 1 can also be considered as a cycle.
As mentioned before, traditionally craving has been seen as a subjective feeling
that could be elicited in external cue-exposure events or internal withdrawal cue ex-
periences. In contrast to traditional viewpoints, in the framework shown in Fig. 1,
craving is not just a subjective feeling, but it is a more complex process which
involves a dynamic cascade of cognitive functions that begin with exposure to cues
and end with behavioral executions. In this extended definition of craving, subjective
feeling of craving, from liking to wanting, is only a part of the whole drug-craving
process, and not the only player in the scene.
Another important aspect of this model is that each block in this figure could be
mainly attributed to a special network in the brain. The striatal-limbic network con-
tributes to bottom-up attentional processing, while dorsal attention network is acti-
vated during the top-down one. The saliency evaluation processing is done by SN,
which has interactions with memory network through memory retrieval processes.
During subjective feeling of craving, the DMN is activated and engages the subject
with internal processes including autobiographical drug-related memories and the
experience of wanting. Finally, ECN contributes to execution or control of behav-
iors. Interactions of different networks in this model can also be interpreted in the
form of imbalanced interaction between neural reward and control circuitry
(Karoly et al., 2013), in which striatal-limbic, default mode, salience and memory
networks are correlated with augmented neural reward circuits, while ECN and at-
tention network contribute to top-down control circuit. These interactions can predict
the final result of particular cue-exposure events. We will describe different interven-
tions using this network-based model in the next section.
6 NEUROCOGNITIVE INTERVENTIONS IN CRAVING-RELATED

PROCESSES
All the theoretical advancements and neuroscience findings in this field will be most
useful when they can be integrated and employed in treatment development. Current
evidence suggests the crucial need for more effective interventional approaches for
addiction therapy. Various interventional strategies for addiction treatment and re-
lapse prevention can be divided into three general categories:
I. Pharmacological interventions, which mostly target subcortical reward-related
circuits, specifically striatal network. Their ultimate goal is to eliminate bottom-up
impulses and emotions for drug intake using withdrawal reducers or to target
impaired executive control with cognitive enhancers (George and Koob, 2010;
Potenza et al., 2011). These interventions mostly block or mimic the reinforcing
effects of drugs, e.g., by affecting the same types of neurotransmitter receptors
as those affected by drugs, or target cognitive deficits in addicted individuals.
Various cognitive enhancers influence neurotransmitters such as glutamate,
6 Neurocognitive interventions in craving-related processes 127
GABA, acetylcholine, and monoamines which modulate cognitive functions

such as attention and response inhibition in prefrontal cortex (Potenza et al., 2012).
These approaches have been fully discussed in other chapters of this volume
(Rezapour et al., 2015).
II. Noninvasive transcranial electrical and magnetic stimulation techniques, which
can change the release of different neurotransmitters in various brain regions,
modify cortical excitability, and modulate the neuronal activity in a region or a
network of the brain (Ekhtiari and Bashir, 2010; Parkin et al., 2015). Therefore,
these techniques might be able to ameliorate the neuroadaptation induced by
chronic drug use and also affect the circuits which mediate addiction-related
cognitive processes such as decision-making and inhibitory control (see
Bellamoli et al., 2014 for a review). Existing and possible applications of this
category of interventions in addiction medicine have been addressed in another
chapter of this volume (Yavari et al., 2015).
III. Cognitive-based (psychological) interventions, such as cognitive-behavioral
therapy and motivational enhancement/motivational interviewing, target both
reward and executive control processes. These interventions have various
pathogenic or healthy cognitive targets and strengthen frontal inhibitory and
executive control, and motivate patients for change (Konova et al., 2013).
Here, we divided main cognitive-based interventions in addiction medicine and in-

troduced their corresponding brain network targets within eight categories, which are
shown in Table 2 and explained in the following.
6.1 ENVIRONMENT ENGINEERING

The environment encompasses a wide range of components such as family and peer
relationships, exposure to different drug-associated, emotional- or stress-inducing
cues, and socioeconomic conditions. These environmental factors can be negative,
such as poor relationship with family members and friends, poverty, difficulties in
workplace, stressful conditions, and exposure to drug stimuli, or positive, such as good
family and peer relations and acceptable socioeconomic status (Sinha, 2001; Solinas
et al., 2010). Different types of drug-related cues (visual, auditory, smell, taste, tactile,
imaginary processes), negative emotional states (anger, anxiety, depression, emotional
distress, etc.), and different stressors (fatigue, hunger, etc.) can induce drug craving by
activating striatal-limbic network and thereby increasing subjects’ vulnerability to
drug taking and relapse (Sinha, 2001). Modifying life conditions of the patients is a
crucial part of their treatment. The first step in craving prevention during abstinence
is to reduce cue exposure and provides a clean and cue-free environment. One step
further would be to provide positive life experiences. These are the main goals pursued
by environment engineering interventions. The DAN, which has been shown to be
overactive during drug cue exposure (Luijten et al., 2011), and striatal-limbic network
which is activated by drug-related cues (Jentsch and Taylor, 1999) are affected by this
category of interventions.
Table 2 Existing Cognitive Interventions Potentially Efficient on Drug Craving

with Their Target Brain Networks
Target Brain
No. Intervention Networks
1 Environment engineering (cue abstinence) L, A

2 Goal setting and motivational enhancement S, EC
3 Behavioral activation (natural reward replacement) L, S
4 Attention training Explicit attention training A, EC
techniques Implicit attention training
Attentional bias modification
Meditation training
5 Mindfulness training Psychoeducation for A, D
metacognition
Interoceptive mindfulness
Mindful craving surfing/
acceptance
6 Reappraisal training Stimulus Internal stimuli S, EC
reappraisal External
stimuli
Action and outcome reappraisal
7 Memory Activating drug-related A, S, M
reconsolidation memories, therefore making
them vulnerable
Modifying episodic drug-related
memories
Cue devaluation (recurrent cue
exposure)
Overwriting drug-related
memories
Modifying compulsive
behaviors (procedural
memories)
8 Effortful active Shifting attention to another EC, A
suppression subject (thought suppression)
Using motor control system for
effortful and voluntary
generation of opposing actions.
Abbreviations: L, striatal-limbic network; A, dorsal attention (top-down) network; S, salience network;
ECN, executive control network; D, default mode network; M, memory networks.
6.2 GOAL SETTING AND MOTIVATIONAL ENHANCEMENT

Motivational interviews and motivational enhancement interventions provide a wide
range of client-centered therapies in which patients set their own goals and manage
their motivation toward these goals. Counselors evoke patients’ intrinsic motivation
6 Neurocognitive interventions in craving-related processes 129
to change, help them to explore and resolve ambivalence, and consolidate a personal
decision and plan for change (Miller and Rollnick, 1991; Smedslund et al., 1996).
These techniques develop a focus in a patient’s life other than their addiction and
improve their commitment to behavioral changes. Motivational interventions help
subjects to control their craving and maintain their abstinence by augmenting
self-referential processing, salience attribution to abstinence, and inhibitory control.
Positive effects of these interventions on craving could be attributed to salience
network and ECN (Ewing et al., 2011).
6.3 BEHAVIORAL ACTIVATION

Behavioral activation (BA) strategies have been widely employed as a major com-
ponent of treatment for depression and other mood disorders. Their goal is to increase
environmental reinforcement and improve patients’ mood and positive affect by en-
gaging them in valued and pleasant activities, such as physical exercising, focusing
on actions related to an important goal, learning new skills, and improving relation-
ship with other people. Modifying sleep and eating habits of patients is also impor-
tant in BA therapy (Hopko et al., 2003; Mazzucchelli et al., 2009). Using BA,
patients are asked to act “outside-in” rather than “inside-out” according to a defined
schedule and independent from their mood (Martell et al., 2013). BA, which targets
striatal-limbic and saliency networks, can be applied as a preventive and promi-
sing adjunct therapeutic approach for drug craving and addiction (MacPherson
et al., 2010).
6.4 ATTENTION TRAINING TECHNIQUES

Drug-related attentional bias is an important characteristic of people with drug use
disorder and is associated with addiction severity, craving, treatment outcome, and
relapse (Hekmat et al., 2011; Marhe et al., 2013; Schoenmakers et al., 2010).
Cognitive remediation strategies in general and attention training techniques in
particular usually employ computerized exercises to strengthen different aspects of
attention and reduce attentional bias toward drug cues. Attention training techniques,
which train subjects to disengage their attention from drug-related stimuli, have been
successfully employed in different studies and resulted in drug consumption de-
crease (Fadardi and Cox, 2009; Schoenmakers et al., 2010; Wiers et al., 2011).
The main target network in this category of interventions could be considered
attention network and ECN.
6.5 MINDFULNESS TRAINING

Mindfulness training and mindfulness-based therapies are systematic training of atten-
tion and self-regulation (Holzel et al., 2011). Mindfulness-based therapies have been
shown to reduce negative mood states such as stress and anxiety, increase positive
emotion, and improve attention, self-control, self-regulation, and metacognitive

awareness. Therefore, they might normalize negative reinforcement processes in
substance-using individuals (e.g., stress-induced craving). Also, they might have pos-
itive effects on some addiction symptoms such as bingeing (Garland et al., 2014;
Potenza et al., 2012; Tang et al., 2007, 2010, 2013). Mindfulness-based therapies mod-
ify activation in different brain areas and networks (Table 2). For example, it has been
shown that they induce changes in ACC, insula, temporo-parietal junction, and fronto-
limbic circuits (Holzel et al., 2011). They also have been shown to induce changes in
white matter integrity in the tract which connects ACC to other brain structures (Tang
et al., 2010); these finding show that mindfulness-based therapies impact the attention
network and DMN (Holzel et al., 2011; Tang et al., 2013; Westbrook et al., 2013).
Considering the absence of prefrontal activation during mindful attention
(Westbrook et al., 2013), these interventions might act through reducing the reactivity
to drug cues rather than cognitive control enhancement.
6.6 REAPPRAISAL TRAINING

Reappraisal is a commonly used form of cognitive regulation for emotion/appetites
including drug craving. Reappraisal training provides the client with deliberate strat-
egies for reinterpreting the meaning of a stimulus, situation, action, or outcome,
usually in order to decrease its emotional/appetitive impact. Various explicit
cognitive coping strategies are employed in reappraisal to reduce the emotional/
appetitive impact of the craving-related situations. During reappraisal, patients try
to use propositional thinking to replace the self-defeating, craving-related thoughts
with more helpful ones (Beadman et al., 2015; Gross, 2002). Reappraisal can act at
different levels, i.e., subjects can consciously devaluate the internal drug-related
stimuli (e.g., hedonic or dysphoric experiences), devaluate external drug-related
stimuli (e.g., drugs, or people, places or things associated with drug use), use possible
harmful outcomes of the drug taking for reappraisal, or use cognitive reappraisal.
Cognitive reappraisal is a type of cognitive change that is used for allocating new
valuation processing. Target brain networks in reappraisal training could include
the salience network and ECN (Staudinger et al., 2009).
6.7 MEMORY RECONSOLIDATION

Memory is one of the most important cognitive functions affected by addiction. Path-
ological associative learning causes compulsive/impulsive drug use despite its
negative consequences. Therefore, memory can be considered an important interven-
tion target. Interventions in this category aim to modify the powerfully remembered
associations between conditioned drug-related cues and drug experience in the brain.
These conditioned drug memories can be interfered with at different levels; recurrent
cue exposure without the associated drug-taking response (unconditioned stimulus)
reduces conditioned responding (extinction). Imagination, written scripts, and live
exposure techniques can be used for exposing the patients to the stimuli associated
with their addictive behavior. This ultimately leads to behavioral desensitization
7 Clinical implications for an integrative neurocognitive model of craving 131
(Kaplan et al., 2011; Volkow et al., 2004). What happens in extinction learning is not
just forgetting a conditional behavior, but is an active learning process which
diminishes the frequency or intensity of conditioned responses to drug cues and ac-
tively reduces the value or salience of drug-related cues and their emotional
responses (Kaplan et al., 2011). One step further is to not only extinguish but also
overwrite drug-related memories with other emotional memories, i.e., to develop
new patterns of healthy behaviors to replace conditioned drug-induced ones
(Bouton, 2004).
The major neural circuits affected by these interventions are considered to be
attention, memory, and salience networks.
6.8 EFFORTFUL ACTIVE SUPPRESSION

Two ends of craving management strategies can be considered “reappraisal” and
“effortful, active suppression.” The former acts on the initial phases of craving gen-
eration process with the main goal of decreasing appetitive experience, while the
latter acts on already elicited impulses with the main goal of decreasing behavioral
expression (Gross, 2002). In suppression, individuals purposefully try to prevent
drug and craving-related thoughts coming to mind. Using the suppression strategy
in dealing with drug craving is very common, yet has some disadvantages such as
lower levels of confidence and more depressive symptoms in patients who use these
strategy (Rogojanski et al., 2011). It might even increase responsivity to drug cues
(Beadman et al., 2015). The ECN is the key network in effortful active suppression.
7 CLINICAL IMPLICATIONS FOR AN INTEGRATIVE

NEUROCOGNITIVE MODEL OF CRAVING
Various pharmacological, cognitive, and NIBS interventions have been proposed to
manage craving and prevent relapse. In spite of their efforts to target some aspects of
drug craving, no existing treatment is completely effective (Dutra et al., 2008; Martin
and Rehm, 2012). Furthermore, there is little evidence regarding interactions of these
interventions and the possibilities for designing multiapproach interventions.
A neurocognitive model of craving may help address this gap in different ways:
1. Individualized treatment planning and monitoring: Drug-taking behaviors are

often considered the final output of drug craving, but the level of correspondence
of different underlying cognitive processes are different in each patient. Since
neural activity during cue exposure has been shown to be a predictor of relapse
following treatment (Janes et al., 2010; Jia et al., 2011), an integrative model
helps us to better understand the functional connectivity between several
networks and their cognitive processes involved in drug craving and substance
use disorders, and also to determine the neurocognitive target of treatments more
specifically. Furthermore, it provides us with an opportunity to use appropriate
assessment tools for evaluating changes during and posttreatment and monitoring
the course of treatments in an individualized manner.
2. Integrated cognitive therapies: As described above, various cognitive therapies
target different processes and underlying networks. Identifying complimentary
combination of cognitive interventions seems a promising strategy for improving
treatment outcomes (Barrowclough et al., 2001; Cavallo et al., 2007).
A neurocognitive model can suggest novel ways to intelligently combine
different cognitive therapies such as cognitive remediation strategies, attentional
bias modifications, and reappraisal trainings with each other in a comprehensive
program to have a more effective psychotherapy package.
3. Multidimensional treatment interventions: A strategy to enhance the
effectiveness of different types of therapies is to combine them with one or more
adjuvant treatments. A neurocognitive model of craving would be able to suggest
novel ways to design multiapproach interventions. These multiapproach
interventions such as a combination of different pharmacological and cognitive
therapies can address weaknesses of each therapy and cover a range of craving
components. NIBS techniques including transcranial electrical and magnetic
stimulation (tES and TMS) are new emerging tools that have shown promise for
the treatment of different neuropsychiatric disorders (Lefaucheur et al., 2014;
Tortella et al., 2015). Several studies have employed a combination of cognitive
therapies and transcranial direct current stimulation (tDCS) (Brunoni et al.,
2014a; Segrave et al., 2014) and pharmacotherapy with tDCS (Brunoni et al.,
2014b) for the treatment of depression, in some cases yielding significant
therapeutic responses. Hence, NIBS techniques can be used combined with
pharmacological and cognitive therapies based on the integrative neurocognitive
mode, augmenting the positive impact of the primary interventions.

It has been long assumed that the isolated operation of single brain areas generates
various functions in the brain (simplified structure–function mapping viewpoint).
Some of these isolated brain regions are connected through direct physical pathways
and form small networks in the brain. An example is the structural connectivity
between dorsolateral prefrontal cortex, as a reflective top-down system, and the
amygdala, as a reflexive bottom-up system, which specifically becomes imbalanced
in addiction. More recent evidence emphasizes the importance of interacting and dis-
tributed brain areas or large-scale brain networks for complex brain functions, such
as memory and language. Nodes of these networks might correspond to neurons,
populations of neurons, or anatomically isolated brain regions. These nodes can
be linked via structural (anatomical), functional (correlational), and/or effective
(causal) connections (Shafi et al., 2012). Development of neuroimaging techniques
and also powerful network modeling tools from graph theory and dynamical systems
have made it feasible to analyze the structure and function of brain networks (Sporns,
8 Conclusions and future directions 133
2013). Finally, it has been suggested that various dynamic cognitive processes in the
brain, such as drug craving, emerge from the interaction and different levels of con-
tribution of these specialized large-scale networks; i.e., specific levels of contribu-
tion and interaction of different networks, such as DMN, SN, and ECN enable the
brain to generate different states and switch between them (Shafi et al., 2012). Each
of these four different viewpoints, regional, small-scale networks, large-scale net-
works, and brain states, which are schematically shown in Fig. 2, provides insights
into the brain function and can be employed for specific applications.
All these advances in cognitive neuroscience have enriched our knowledge of
brain function and raised serious hopes for an evolution in the understanding and
treatment of neuropsychological disorders and specifically substance use disorder.
Currently, addiction medicine is mostly focused on behavioral outputs, such as drug
abstinence and reducing high-risk behaviors in different therapeutic processes; but
research in recent years suggests that this approach is not able to cover all potentially
important aspects of addiction treatment. Attention to the cognitive roots of behavior
suggests an extended spectrum of interventions for addiction medicine. In light of
accumulated knowledge about addiction neurobiology, developing an integrative
model of drug craving can help us to reach more successful results in relapse preven-
tion and craving management. More future studies are needed to determine the in-
terventions based on this model and also suggest tools for evaluation and monitoring
of treatment outcomes.
FIGURE 2
Four levels of approach to the neural correspondence of drug craving. (1) Regional models,
(2) small-scale network models, (3) large-scale network models, and (4) brain state models
with weighted contribution of the large-scale networks. Brain activities related to different
cognitive components of drug craving can be studied in “Static” or “Time Variant and
Dynamic” modes in these levels. All these models are wrong in terms of depicting the
complete nature of this phenomenon, but they are all useful to make implications in addiction
medicine.
REFERENCES
Anton, R.F., 1999. What is craving? Models and implications for treatment. Alcohol Res.
Health 23 (3), 165–173.
Barrowclough, C., et al., 2001. Randomized controlled trial of motivational interviewing, cog-
nitive behavior therapy, and family intervention for patients with comorbid schizophrenia
and substance use disorders. Am. J. Psychiatry 158 (10), 1706–1713.
Beadman, M., et al., 2015. A comparison of emotion regulation strategies in response to crav-
ing cognitions: effects on smoking behaviour, craving and affect in dependent smokers.
Behav. Res. Ther. 69, 29–39. Retrieved, http://linkinghub.elsevier.com/retrieve/pii/
S0005796715000522.
Bechara, A., 2005. Decision making, impulse control and loss of willpower to resist drugs: a
neurocognitive perspective. Nat. Neurosci. 8 (11), 1458–1463.
Bellamoli, E., et al., 2014. RTMS in the treatment of drug addiction: an update about human
studies. Behav. Neurol. 2014, 815215. Retrieved, http://www.pubmedcentral.nih.gov/
articlerender.fcgi?artid¼4006612&tool¼pmcentrez&rendertype¼abstract.
Bonson, K.R., et al., 2002. Neural systems and cue-induced cocaine craving.
Bouton, M.E., 2004. Context and behavioral processes in extinction. Learn. Mem. 11 (5),
485–494.
Brody, A.L., et al., 2002. Brain metabolic changes during cigarette craving. Arch. Gen. Psy-
chiatry 59 (12), 1162–1172.
Broyd, S.J., et al., 2009. Default-mode brain dysfunction in mental disorders: a systematic re-
view. Neurosci. Biobehav. Rev. 33 (3), 279–296.
Brunoni, A.R., et al., 2014a. Cognitive control therapy and transcranial direct current stimulation
for depression: a randomized, double-blinded, controlled trial. J. Affect. Disord. 162, 43–49.
Brunoni, A.R., et al., 2014b. Differential improvement in depressive symptoms for tDCS alone
and combined with pharmacotherapy: an exploratory analysis from the sertraline vs. elec-
trical current therapy for treating depression clinical study. Int. J. Neuropsychopharmacol.
17 (1), 53–61.
Cavallo, D.A., et al., 2007. Combining cognitive behavioral therapy with contingency man-
agement for smoking cessation in adolescent smokers: a preliminary comparison of two
different CBT formats. Am. J. Addict. 16 (6), 468–474.
Charboneau, E.J., et al., 2013. Cannabis cue-induced brain activation correlates with drug
craving in limbic and visual salience regions: preliminary results. Psychiatry Res.
214 (2), 122–131.
Chase, H.W., Eickhoff, S.B., Laird, A.R., Lee, H., 2011. The neural basis of drug stimulus
processing and craving: an activation likelihood estimation meta-analysis. Biol. Psychia-
try 70 (8), 785–793.
Cloutman, L.L., Binney, R.J., Drakesmith, M., Parker, G.J.M., Lambon Ralph, M.A., 2012.
The variation of function across the human insula mirrors its patterns of structural connec-
tivity: evidence from in vivo probabilistic tractography. NeuroImage 59 (4), 3514–3521.
Cole, D.M., et al., 2010. Nicotine replacement in abstinent smokers improves cognitive with-
drawal symptoms with modulation of resting brain network dynamics. NeuroImage 52 (2),
590–599.
Corbetta, M., Shulman, G.L., 2002. Control of goal-directed and stimulus-driven attention in
the brain. Nat. Rev. Neurosci. 3 (3), 201–215.
References 135
Courtney, K.E., Ghahremani, D.G., Ray, L.A., 2015. The effect of alcohol priming on neural
markers of alcohol cue-reactivity. Am. J. Drug Alcohol Abuse 41, 300–308.
Cox, W.M., Fadardi, J.S., Intriligator, J.M., Klinger, E., 2014. Attentional bias modification
for addictive behaviors: clinical implications. CNS Spectr. 19 (3), 215–224.
Dackis, C.A., Kampman, K.M., Lynch, K.G., Pettinati, H.M., O’Brien, C.P., 2005. A double-
blind, placebo-controlled trial of modafinil for cocaine dependence.
David, S.P., et al., 2007. Effects of acute nicotine abstinence on cue-elicited ventral striatum/
nucleus accumbens activation in female cigarette smokers: a functional magnetic reso-
nance imaging study. Brain Imaging Behav. 1 (3–4), 43–57.
DeWitt, S.J., Ketcherside, A., McQueeny, T.M., Dunlop, J.P., Filbey, F.M., 2015. The hyper-
sentient addict: an exteroception model of addiction. Am. J. Drug Alcohol Abuse 41 (5),
374–381.
Dosenbach, N.U.F., et al., 2007. Distinct brain networks for adaptive and stable task control in
humans. Proc. Natl. Acad. Sci. U. S. A. 104 (26), 11073–11078.
Drummond, D.C., 2001. Theories of drug craving, ancient and modern. Addiction 96 (1),
33–46.
Due, D.L., Huettel, S.A., Hall, W.G., Rubin, D.C., 2002. Activation in mesolimbic and visuo-
spatial neural circuits elicited by smoking cues: evidence from functional magnetic reso-
nance imaging. Am. J. Psychiatr. 159 (6), 954–960.
Dutra, L., et al., 2008. A meta-analytic review of psychosocial interventions for substance use
disorders. Am. J. Psychiatry 165 (2), 179–187.
Eichele, T., et al., 2008. Prediction of human errors by maladaptive changes in event-related
brain networks. Proc. Natl. Acad. Sci. U.S.A. 105 (16), 6173–6178.
Ekhtiari, H., 2010. Addiction studies in Iran; neuroscientists need to do more. Basic Clin. Neu-
rosci. 1 (3), 3–4.
Ekhtiari, H., Bashir, S., 2010. Brain stimulation technology in addiction medicine; main prob-
lems waiting for solutions. Basic Clin. Neurosci. 1 (4), 3–4.
Ekhtiari, H., et al., 2008. Functional neuroimaging study of brain activation due to craving in
heroin intravenous users. Iran. J. Psychiatry Clin. Psychol. 14, 269–280.
Engelmann, J.M., et al., 2012. Neural substrates of smoking cue reactivity: a meta-analysis of
fMRI studies. NeuroImage 60 (1), 252–262.
actions to habits to compulsion. Nat. Neurosci. 8 (11), 1481–1489.
Ewing, F., Sarah, W., Filbey, F.M., Hendershot, C.S., McEachern, A.D., Hutchison, K.E.,
2011. Proposed model of the neurobiological mechanisms underlying psychosocial alco-
hol interventions: the example of motivational interviewing. J. Stud. Alcohol Drugs
72, 903–916.
Fadardi, J.S., Cox, W.M., 2009. Reversing the sequence: reducing alcohol consumption by
overcoming alcohol attentional bias. Drug Alcohol Depend. 101, 137–145.
Field, M., Cox, W.M., 2008. Attentional bias in addictive behaviors: a review of its develop-
ment, causes, and consequences. Drug Alcohol Depend. 97 (1–2), 1–20.
Field, M., Marhe, R., Franken, I.H.A., 2014. The clinical relevance of attentional bias in sub-
stance use disorders. CNS Spectr. 19 (3), 225–230.
Floresco, S.B., Blaha, C.D., Yang, C.R., Phillips, A.G., 2001. Modulation of hippocampal and
amygdalar-evoked activity of nucleus accumbens neurons by dopamine: cellular mecha-
nisms of input selection. J. Neurosci. 21 (8), 2851–2860.
Fox, M.D., Buckner, R.L., White, M.P., Greicius, M.D., Pascual-Leone, A., 2012. Efficacy of
transcranial magnetic stimulation targets for depression is related to intrinsic functional
connectivity with the subgenual cingulate. Biol. Psychiatry 72 (7), 595–603.
Franken, I.H.A., 2003. Drug craving and addiction: integrating psychological and neuropsy-
chopharmacological approaches. Prog. Neuropsychopharmacol. Biol. Psychiatry 27 (4),
563–579.
Garavan, H., et al., 2000. Cue-induced cocaine craving: neuroanatomical specificity for drug
users and drug stimuli. Am. J. Psychiatry 157 (11), 1789–1798.
Garland, E.L., Froeliger, B., Howard, M.O., 2014. Mindfulness training targets neurocognitive
mechanisms of addiction at the attention-appraisal-emotion interface. Front. Psychiatry
4, 1–16.
George, O., Koob, G.F., 2010. Individual differences in prefrontal cortex function and the
transition from drug use to drug dependence. Neurosci. Biobehav. Rev. 35 (2),
232–247. Retrieved July 11, 2015. http://www.pubmedcentral.nih.gov/articlerender.
fcgi?artid¼2955797&tool¼pmcentrez&rendertype¼abstract.
Goldstein, R.Z., et al., 2007. Role of the anterior cingulate and medial orbitofrontal cortex in
processing drug cues in cocaine addiction. Neuroscience 144 (4), 1153–1159.
Gorelick, D.A., Zangen, A., George, M.S., 2014. Transcranial magnetic stimulation in the
treatment of substance addiction. Ann. N. Y. Acad. Sci. 1327, 79–93.
Goudriaan, A.E., de Ruiter, M.B., van den Brink, W., Oosterlaan, J., Veltman, D.J., 2010. Brain
activation patterns associated with cue reactivity and craving in abstinent problem gamblers,
heavy smokers and healthy controls: an fMRI study. Addict. Biol. 15 (4), 491–503.
Grant, S., et al., 1996. Activation of memory circuits during cue-elicited cocaine craving. Proc.
Natl. Acad. Sci. U.S.A. 93 (21), 12040–12045.
Gross, J.J., 2002. Emotion regulation: affective, cognitive, and social consequences.
Psychophysiology 39 (3), 281–291.
Hekmat, S., et al., 2011. Cognitive flexibility, attention and speed of mental processing in opioid
and methamphetamine addicts in comparison with non-addicts. Basic Clin. Neurosci.
2, 12–19. Retrieved, http://bcn.iums.ac.ir/browse.php?a_code¼A-10-2-15&slc_lang¼en&
sid¼1.
Hoelscher, T.J., Klinger, E., Barta, S.G., 1981. Incorporation of concern- and nonconcern-
related verbal stimuli into dream content. J. Abnorm. Psychol. 90 (1), 88–91.
Holzel, B.K., et al., 2011. How does mindfulness meditation work? Proposing mechanisms of
action from a conceptual and neural perspective. Perspect. Psychol. Sci. 6, 537–559.
Hopko, D.R., Lejuez, C.W., Ruggiero, K.J., Eifert, G.H., 2003. Contemporary behavioral ac-
tivation treatments for depression: procedures, principles, and progress. Clin. Psychol.
Rev. 23 (5), 699–717. Retrieved June 22, 2015 http://www.ncbi.nlm.nih.gov/pubmed/
12971906.
Janes, A.C., et al., 2010. Brain reactivity to smoking cues prior to smoking cessation predicts
ability to maintain tobacco abstinence. Biol. Psychiatry 67 (8), 722–729.
Janes, A.C., Farmer, S., Peechatka, A.L., Frederick, B. de B., Lukas, S.E., 2015. Insula-dorsal
anterior cingulate cortex coupling is associated with enhanced brain reactivity to smoking
cues. Neuropsychopharmacology 40 (7), 1561–1568.
neural reactivity to drug cues in addiction: a survey of human neuroimaging studies.
Neurosci. Biobehav. Rev. 38 (1), 1–16.
References 137
cology (Berl.) 146 (4), 373–390. Retrieved, http://www.ncbi.nlm.nih.gov/pubmed/
10550488.
Jia, Z., et al., 2011. An initial study of neural responses to monetary incentives as related to
treatment outcome in cocaine dependence. Biol. Psychiatry 70 (6), 553–560.
Johansson, B.A., Berglund, M., Lindgren, A., 2006. Efficacy of maintenance treatment
with naltrexone for opioid dependence: a meta-analytical review. Addiction 101 (4),
491–503.
Kaplan, G.B., Heinrichs, S.C., Carey, R.J., 2011. Treatment of addiction and anxiety using
extinction approaches: neural mechanisms and their treatment implications. Pharmacol.
Biochem. Behav. 97 (3), 619–625. Retrieved http://dx.doi.org/10.1016/j.pbb.2010.08.004.
Karoly, H.C., Harlaar, N., Hutchison, K.E., 2013. Substance use disorders: a theory-driven
approach to the integration of genetics and neuroimaging. Ann. N. Y. Acad. Sci.
1282 (1), 71–91.
Kassel, J.D., Shiffman, S., 1992. What can hunger teach us about drug craving? A comparative
analysis of the two constructs. Adv. Behav. Res. Ther. 14 (3), 141–167.
Kilts, C.D., et al., 2001. Neural activity related to drug craving in cocaine addiction. Arch.
Gen. Psychiatry 58 (4), 334.
Konova, A.B., Moeller, S.J., Goldstein, R.Z., 2013. Common and distinct neural targets of
treatment: changing brain function in substance addiction. Neurosci. Biobehav. Rev.
37 (10 Pt. 2), 2806–2817. Retrieved August 14, 2015. http://www.sciencedirect.com/sci
ence/article/pii/S0149763413002261.
Krmpotich, T.D., et al., 2013. Resting-state activity in the left executive control network is
associated with behavioral approach and is increased in substance dependence. Drug Al-
cohol Depend. 129 (1–2), 1–7.
Larimer, M.E., Palmer, R.S., Marlatt, G.A., 1999. Relapse prevention. An overview of Mar-
latt’s cognitive-behavioral model. Alcohol Res. Health 23 (2), 151–160.
Lefaucheur, J.-P., et al., 2014. Evidence-based guidelines on the therapeutic use of repetitive
transcranial magnetic stimulation (rTMS). Clin. Neurophysiol. 125 (11), 2150–2206.
Lerman, C., et al., 2014. Large-scale brain network coupling predicts acute nicotine abstinence
effects on craving and cognitive function. JAMA Psychiatry 71 (5), 523–530.
Lou, M., Wang, E., Shen, Y., Wang, J., 2012. Cue-elicited craving in heroin addicts at different
abstinent time: an fMRI pilot study. Subst. Use Misuse 47 (6), 631–639.
Lubman, D.I., Yücel, M., Pantelis, C., 2004. Addiction, a condition of compulsive behaviour?
Neuroimaging and neuropsychological evidence of inhibitory dysregulation. Addiction
99 (12), 1491–1502.
Ludwig, A.M., Wikler, A., Stark, L.H., 1974. The first drink: psychobiological aspects of crav-
ing. Arch. Gen. Psychiatry 30 (4), 539–547.
Luijten, M., et al., 2011. Neurobiological substrate of smoking-related attentional bias.
NeuroImage 54 (3), 2374–2381.
Maarefvand, M., Ghiasvand, H.R., Ekhtiari, H., 2013. Drug craving terminology among opiate
dependents; a mixed method study. Iran. J. Psychiatry 8, 97–103.
MacPherson, L., et al., 2010. Randomized controlled trial of behavioral activation smoking
cessation treatment for smokers with elevated depressive symptoms. J. Consult. Clin. Psy-
chol. 78, 55–61.
Marhe, R., Luijten, M., van de Wetering, B.J., Smits, M., Franken, I.H., 2013. Individual dif-
ferences in anterior cingulate activation associated with attentional bias predict cocaine
use after treatment. Neuropsychopharmacology 38 (6), 1085–1093. Retrieved, http://dx.

doi.org/10.1038/npp.2013.7.
Martell, C.R., Dimidjian, S., Herman-Dunn, R., 2013. Behavioral Activation for Depression:
A Clinician’s Guide. Guilford Press, New York.
Martin, G.W., Rehm, J., 2012. The effectiveness of psychosocial modalities in the treatment
of alcohol problems in adults: a review of the evidence. Can. J. Psychiatry 57 (6),
350–358.
Mazzucchelli, T., Kane, R., Rees, C., 2009. Behavioral Activation Treatments for Depression
in Adults: A Meta-Analysis and Review. Retrieved June 22, 2015. http://www.ncbi.nlm.
nih.gov/books/PMH0027573/.
McBride, D., Barrett, S.P., Kelly, J.T., Aw, A., Dagher, A., 2006. Effects of expectancy and
abstinence on the neural response to smoking cues in cigarette smokers: an fMRI study.
McClernon, F.J., Kozink, R.V., Lutz, A.M., Rose, J.E., 2009. 24-H smoking abstinence poten-
tiates fMRI-BOLD activation to smoking cues in cerebral cortex and dorsal striatum.
Mel’nikov, M.E., et al., 2014. Dynamic mapping of the brain in substance-dependent individ-
uals: functional magnetic resonance imaging. Bull. Exp. Biol. Med. 158 (2), 260–263.
Menon, V., 2011. Large-scale brain networks and psychopathology: a unifying triple network
model. Trends Cogn. Sci. 15 (10), 483–506.
Miller, W.R., Rollnick, S., 1991. Motivational Interviewing: Preparing People to Change Ad-
dictive Behavior. Guilford Press, New York.
Miquel, M., Toledo, R., Garcı́a, L.I., Coria-Avila, G.A., Manzo, J., 2009. Why should we keep
the cerebellum in mind when thinking about addiction? Curr. Drug Abuse Rev. 2 (1),
26–40.
Moeller, S.J., et al., 2014. Functional, structural, and emotional correlates of impaired insight
in cocaine addiction. JAMA Psychiatry 71 (1), 61–70.
Müller-Oehring, E.M., et al., 2013. Midbrain-driven emotion and reward processing in alco-
holism. Neuropsychopharmacology 38 (10), 1844–1853.
Park, M.-S., et al., 2007. Brain substrates of craving to alcohol cues in subjects with alcohol use
disorder. Alcohol Alcohol. 42 (5), 417–422.
Parkin, B.L., Ekhtiari, H., Walsh, V.F., 2015. Non-invasive human brain stimulation in cog-
nitive neuroscience: a primer. Neuron 87 (5), 932–945. Retrieved September 3, 2015.
http://www.sciencedirect.com/science/article/pii/S0896627315006741.
Potenza, M.N., Sofuoglu, M., Carroll, K.M., Rounsaville, B.J., 2011. Neuroscience of behav-
ioral and pharmacological treatments for addictions. Neuron 69 (4), 695–712. Retrieved
July 11, 2015. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid¼3063555&
tool¼pmcentrez&rendertype¼abstract.
Potenza, M.N., Sofuoglu, M., Carroll, K.M., Rounsaville, B.J., 2012. Neuroscience of behav-
ioral and pharmacological treatments for addictions. Neuron 69 (4), 695–712.
Potvin, S., Tikàsz, A., Dinh-Williams, L.L.-A., Bourque, J., Mendrek, A., 2015. Cigarette
cravings, impulsivity, and the brain. Front. Psychiatry 6, 125.
Prisciandaro, J.J., et al., 2014. The relationship between years of cocaine use and brain acti-
vation to cocaine and response inhibition cues. Addiction 109 (12), 2062–2070.
Rezapour, T., DeVito, E.E., Sofuoglu, M., Ekhtiari, H., 2015. Perspectives on neurocognitive
rehabilitation as an adjunct treatment for addictive disorders: from cognitive improvement
to relapse prevention. In: Ekhtiari, H., Paulus, M. (Eds.), Progress in Brain Research.
Elsevier, Netherlands. [Epub ahead of Print].
References 139
Robbins, T.W., Ersche, K.D., Everitt, B.J., 2008. Drug addiction and the memory systems of
the brain. Ann. N. Y. Acad. Sci. 1141, 1–21.
sensitization theory of addiction. Brain Res. Brain Res. Rev. 18 (3), 247–291.
Robinson, T.E., Berridge, K.C., 2008. The incentive sensitization theory of addiction: some
current issues. Philos. Trans. R Soc. Lond. B Biol. Sci. 363 (1507), 3137–3146.
Rogojanski, J., Vettese, L.C., Antony, M.M., 2011. Coping with cigarette cravings: compar-
ison of suppression versus mindfulness-based strategies. Mindfulness 2 (1), 14–26.
Sara, S.J., Segal, M., 1991. Plasticity of sensory responses of locus coeruleus neurons in the
behaving rat: implications for cognition. Prog. Brain Res. 88, 571–585.
Sayette, M.A., et al., 2000. The measurement of drug craving. Addiction 95 (Suppl. 2),
S189–S210.
Schoenmakers, T.M., et al., 2010. Clinical effectiveness of attentional bias modification
training in abstinent alcoholic patients. Drug Alcohol Depend. 109 (1–3), 30–36.
Retrieved, http://dx.doi.org/10.1016/j.drugalcdep.2009.11.022.
Schultz, W., 2007. Behavioral dopamine signals. Trends Neurosci. 30 (5), 203–210.
Seeley, W.W., et al., 2007. Dissociable intrinsic connectivity networks for salience processing
and executive control. J. Neurosci. 27 (9), 2349–2356.
Segrave, R.A., Arnold, S., Hoy, K., Fitzgerald, P.B., 2014. Concurrent cognitive control train-
ing augments the antidepressant efficacy of tDCS: a pilot study. Brain Stimul. 7 (2),
325–331.
Selden, N.R., Everitt, B.J., Jarrard, L.E., Robbins, T.W., 1991. Complementary roles for the
amygdala and hippocampus in aversive conditioning to explicit and contextual cues.
Neuroscience 42 (2), 335–350.
Seo, D., Sinha, R., 2014. The neurobiology of alcohol craving and relapse. Handb. Clin. Neu-
rol. 125, 355–368.
Shackman, A.J., et al., 2011. The integration of negative affect, pain and cognitive control in
the cingulate cortex. Nat. Rev. Neurosci. 12 (3), 154–167.
Shafi, M.M., Brandon Westover, M., Fox, M.D., Pascual-Leone, A., 2012. Exploration and
modulation of brain network interactions with noninvasive brain stimulation in combina-
tion with neuroimaging. Eur. J. Neurosci. 35, 805–825.
Shahbabaie, A., et al., 2014. State dependent effect of transcranial direct current stimu-
lation (tDCS) on methamphetamine craving. Int. J. Neuropsychopharmacol. 17 (10),
1591–1598.
Shariatirad, S., Maarefvand, M., Ekhtiari, H., 2013. Emergence of a methamphetamine crisis
in Iran. Drug Alcohol Rev. 32 (2), 223–224.
Siegel, S., 1989. Pharmacological Conditioning and Drug Effects. Humana Press,
pp. 115–180.
Singleton, E.G., Gorelick, D.A., 1998. Mechanisms of alcohol craving and their clinical
implications. In: Galanter, M. (Ed.), Recent Developments in Alcoholism. Springer US,
Boston, MA, pp. 177–195.
Sinha, R., 2001. How does stress increase risk of drug abuse and relapse?
Psychopharmacology 158, 343–359.
Smedslund, G., et al., 1996. Cochrane Database of Systematic Reviews. John Wiley & Sons,
Ltd., Chichester, UK.
Smolka, M.N., et al., 2006. Severity of nicotine dependence modulates cue-induced brain ac-
tivity in regions involved in motor preparation and imagery. Psychopharmacology
184 (3–4), 577–588.
Solinas, M., Thiriet, N., Chauvet, C., Jaber, M., 2010. Prevention and treatment of drug addiction
by environmental enrichment. Prog. Neurobiol. 92 (4), 572–592. Retrieved September 13,
2015. http://www.sciencedirect.com/science/article/pii/S0301008210001450.
Sporns, O., 2013. Structure and function of complex brain networks. Dialogues Clin. Neurosci.
15 (3), 247–262.
Staudinger, M.R., Erk, S., Abler, B., Walter, H., 2009. Cognitive reappraisal modulates
expected value and prediction error encoding in the ventral striatum. NeuroImage
47 (2), 713–721. Retrieved September 13, 2015. http://www.sciencedirect.com/science/ar
ticle/pii/S1053811909004844.
Stewart, J., de Wit, H., Eikelboom, R., 1984. Role of unconditioned and conditioned drug ef-
fects in the self-administration of opiates and stimulants. Psychol. Rev. 91 (2), 251–268.
Sutherland, M.T., McHugh, M.J., Pariyadath, V., Stein, E.A., 2012. Resting state functional
connectivity in addiction: lessons learned and a road ahead. NeuroImage 62 (4),
2281–2295.
Tabatabaei-Jafari, H., et al., 2014. Patterns of brain activation during craving in heroin depen-
dents successfully treated by methadone maintenance and abstinence-based treatments.
J. Addict. Med. 8, 123–129.
Tang, Y.-Y., et al., 2007. Short-term meditation training improves attention and self-
regulation. Proc. Natl. Acad. Sci. U.S.A. 104 (43), 17152–17156.
Tang, Y.-Y., et al., 2010. Short-term meditation induces white matter changes in the anterior
cingulate. Proc. Natl. Acad. Sci. U.S.A. 107 (35), 15649–15652.
Tang, Y.-Y., Tang, R., Posner, M.I., 2013. Brief meditation training induces smoking reduction.
Proc. Natl. Acad. Sci. U.S.A. 110 (34), 13971–13975. Retrieved, http://www.pubmedcentral.
nih.gov/articlerender.fcgi?artid¼3752264&tool¼pmcentrez&rendertype¼abstract.
Tiffany, S.T., 1990. A cognitive model of drug urges and drug-use behavior: role of automatic
and nonautomatic processes. Psychol. Rev. 97 (2), 147–168.
Tortella, G., et al., 2015. Transcranial direct current stimulation in psychiatric disorders.
World J. Psychiatry 5 (1), 88–102.
Volkow, N.D., Fowler, J.S., Wang, G.J., 2004. The addicted human brain viewed in the light of
imaging studies: brain circuits and treatment strategies. Neuropharmacology 47 (Suppl. 1),
3–13.
Volkow, N.D., et al., 2006. Cocaine cues and dopamine in dorsal striatum: mechanism of crav-
ing in cocaine addiction. J. Neurosci. 26 (24), 6583–6588.
Volkow, N.D., Baler, R.D., Goldstein, R.Z., 2011. Addiction: pulling at the neural threads of
social behaviors. Neuron 69 (4), 599–602.
Waters, A.J., et al., 2003. Attentional bias predicts outcome in smoking cessation. Health
Psychol. 22 (4), 378–387.
Wang, G.J., et al., 1999. Regional brain metabolic activation during craving elicited by recall
of previous drug experiences. Life Sci. 64 (9), 775–784.
Wang, Y., et al., 2013. Altered fronto-striatal and fronto-cerebellar circuits in heroin-
dependent individuals: a resting-state FMRI study. PLoS One 8 (3), e58098.
Westbrook, C., et al., 2013. Mindful attention reduces neural and self-reported cue-induced
craving in smokers. Soc. Cogn. Affect. Neurosci. 8, 73–84.
Westerberg, C.E., Miller, B.B., Reber, P.J., Cohen, N.J., Paller, K.A., 2011. Neural correlates
of contextual cueing are modulated by explicit learning. Neuropsychologia 49 (12),
3439–3447.
References 141
Wiers, R.W., Eberl, C., Rinck, M., Becker, E.S., Lindenmeyer, J., 2011. Retraining automatic
action tendencies changes alcoholic patients’ approach bias for alcohol and improves treat-
ment outcome. Psychol. Sci. 22, 490–497.
Witkiewitz, K., Marlatt, G.A., Walker, D., 2005. Mindfulness-based relapse prevention for
alcohol and substance use disorders. J. Cogn. Psychother. 19 (3), 211–228.
Yalachkov, Y., Kaiser, J., Naumer, M.J., 2009. Brain regions related to tool use and action
knowledge reflect nicotine dependence. J. Neurosci. 29 (15), 4922–4929.
Yalachkov, Y., Kaiser, J., Naumer, M.J., 2010. Sensory and motor aspects of addiction. Behav.
Brain Res. 207 (2), 215–222.
Yavari, F., et al., 2015. Noninvasive brain stimulation for addiction medicine: from monitoring
to modulation. In: Ekhtiari, H., Paulus, M. (Eds.), Progress in Brain Research. Elsevier,
Netherlands.
CHAPTER
Response inhibition and

addiction medicine: from
use to abstinence
Philip A. Spechler*,†,1, Bader Chaarani*, Kelsey E. Hudson†, Alexandra Potter*,†,
8
John J. Foxe{,}, Hugh Garavan*,†
*Department of Psychiatry, Vermont Center on Behavior and Health, University of Vermont,
Burlington, VT, USA
†
{
Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
}
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA
1
Corresponding author: Tel.: +1-802-656-3774, e-mail address: [email protected]
Abstract
Historically, neuroscientific research into addiction has emphasized affective and reinforce-
ment mechanisms as the essential elements underlying the pursuit of drugs, their abuse,
and difficulties associated with abstinence. However, research over the last decade or so
has shown that cognitive control systems, associated largely but not exclusively with the fron-
tal lobes, are also important contributors to drug use behaviors. Here, we focus on inhibitory
control and its contribution to both current use and abstinence. A body of evidence points to
impaired inhibitory abilities across a range of drugs of abuse. Typically, studies suggest that
substance-abusing individuals are characterized by relative hypoactivity in brain systems un-
derlying inhibitory control. In contrast, abstinent users tend to show either normal or super-
normal levels of activity in the same systems attesting to the importance of inhibitory
control in suppressing the drug use urges that plague attempts at abstinence. In this chapter,
the brain and behavioral basis of response inhibition will be reviewed, with a focus on neu-
roimaging studies of response inhibition in current and abstinent drug abusers.
Keywords
Response inhibition, Addiction, Abstinence, Neuroimaging
1 INTRODUCTION
A defining characteristic of addiction is the loss of control over one’s behavior. It is
central to the diagnosis of a substance use disorder, it is characteristic of the all-too-
common relapses of abstinent users attempting to stay clean, and it is apparent when
143
144 CHAPTER 8 Response inhibition and addiction medicine
initial intentions to have just one drink escalate into a binge drinking session. Al-
though hedonic processes such as liking and craving may form the core motivation
to consume drugs, certain cognitive processes, such as attention and memory, likely
contribute to these drives whereas others, such as response inhibition, likely contrib-
ute to the individual’s efforts to resist these drives. For instance, Bechara’s cognitive
theory of addiction posits that the augmented bottom-up signal of appetitive salience
for drugs, in part, attenuates top-down inhibitory control (Bechara, 2005).
Cognitive control processes, also commonly referred to as executive functions,
are attentionally demanding, and consciously available, volitional processes that ini-
tiate a certain action or interrupt ongoing actions (Atkinson and Shiffrin, 1968;
Schneider and Shiffrin, 1977; Shiffrin and Schneider, 1977). Cognitive control takes
on many forms, including, but not limited to, attentional control and inhibitory con-
trol. Attentional control involves the interaction between perceiving environmental
cues and the allocation of perceptual processing resources (Norman and Shallice,
1985) whereas inhibitory control broadly refers to counteracting behaviors preced-
ing, accompanying, or resulting from cues. With regard to addiction, initiation of
drug cravings may involve mechanisms by which stimuli associated with previous
drug use are detected and processed (Grant et al., 1996; Hester et al., 2006), while
the inhibition of behavior may involve mechanisms related to monitoring and reg-
ulation (Forman et al., 2004; Kaufman et al., 2003). This chapter will focus on in-
hibitory control, largely operationalized as response inhibition, and its
contribution to substance abuse. Specifically, response inhibition will be considered
as a means to characterize substance use, abstinence, and recovery in substance-
dependent individuals.
2 RESPONSE INHIBITION TASKS

Inhibitory control is broadly conceptualized as the ability to suppress or countermand
a thought, action, or feeling. Many investigators study inhibitory control using care-
fully designed tasks like the stop-signal task, or the go/no-go task, that measure an
individual’s ability to suppress a prepotent motor response. During the stop-signal
task, subjects perform a primary task such as identifying with button-press responses
if a visually presented arrow (the target stimulus) points to the left or the right. On a
minority of trials, often one quarter of trials, a unique auditory or visual stimulus (the
stop-signal) follows the target and instructs the subject to countermand their re-
sponse. Task difficulty is manipulated by varying the delay between the target
and stop stimulus, such that the longer the delay the more difficult it is to inhibit
the response. By calculating how fast subjects respond on trials without a stop-signal
and the average stop-signal delay on trials in which they successful inhibit 50% of the
time, one can estimate the speed of the response inhibition process known as the stop-
signal reaction time (SSRT) (Logan and Cowan, 1984). During go/no-go tasks, sub-
jects are presented with a continuous stream of stimuli, the majority of which require
a button-press response (go trial), and a minority requiring no response (no-go trial)
3 The neurobiology of control 145
with the inhibitory demand being induced through the prepotency to respond even on
no-go trials. While both tasks are arguably very rudimentary examples of inhibitory
control, there is evidence, outlined below, that the neural circuitry subserving re-
sponse inhibition is also involved in other types of cognitive and emotional inhibi-
tion, thereby indicating that they may serve as reasonable probes for more complex
inhibitory demands, including those related to resisting drugs. As the neural circuitry
of response inhibition is relatively well understood and yields reliable and sensitive
behavioral measures of inhibitory ability, it has generated a significant number of
studies focused on the role of response inhibition in addiction (Luijten et al.,
2014; Smith et al., 2014).
3 THE NEUROBIOLOGY OF CONTROL

Neuroimaging research has identified the dorsolateral prefrontal cortex (dlPFC) as a
brain region critical for cognitive control. Evidence suggests the dlPFC is implicated
during dual-task coordination (D’Esposito et al., 1995; Mansouri et al., 2009), task
switching (Badre and Wagner, 2006; Dove et al., 2000; Sohn et al., 2000), memory
updating (Edin et al., 2009; Salmon et al., 1996), and response sequencing, monitor-
ing, and manipulation (Kim et al., 2013; Owen et al., 1996). This is consistent with
the human lesion literature implicating the frontal lobes in organizing, regulating,
and producing coherent behavior (Luria and Pribram, 1973; Stuss and Frank
Benson, 1987). Frontal lobe-damaged patients appear to lose important aspects of
autonomous cognitive control as evidenced by the loss of behavioral control to en-
vironmental contingencies (e.g., capture errors and utilization behaviors; Lhermitte,
1986). Although the focus of this review will be on prefrontal systems mediating
control, these systems operate in conjunction with extensive parietal, premotor, cin-
gulate, subcortical, and cerebellar networks. Further, despite the evidence implicat-
ing the frontal lobes in cognitive control, the assignment of specific frontal loci to
specific functions is far from resolved due, perhaps, to one of the defining charac-
teristics of the frontal lobes being their ability to flexibly adapt to task demands.
Dosenbach and colleagues suggest that different brain networks are involved in dis-
tinct aspects of control with the frontoparietal cortex implicated in initiating and
adapting behavior, while sustained stable task performance is associated with the an-
terior cingulate cortex (ACC), anterior insula, frontal operculum, and anterior pre-
frontal cortex (Dosenbach et al., 2007).
With a specific focus on inhibitory control, a body of research (lesion, transcra-
nial magnetic stimulation (TMS), and fMRI methodologies) implicates the right in-
ferior frontal cortex (rIFC) in motor response inhibition (Aron et al., 2003; Chambers
et al., 2006; Garavan et al., 1999, 2006). More broadly, the rIFC is one node of a
motor inhibition network which also includes the pre-supplementary motor area
(pre-SMA), and subthalamic nucleus (STN) (Aron et al., 2014). It is unclear about
the exact causal pathways of these regions (Duann et al., 2009; Neubert et al., 2010;
Swann et al., 2012), but research proposes that the STN receives input from both the
rIFC and pre-SMA, and the STN inhibits motor activity at the basal ganglia (Aron
and Poldrack, 2006; Schmidt et al., 2013). Figure 1 shows a number of the main cor-
tical areas activated during response inhibition from the largest neuroimaging study
of the STOP task (Whelan et al., 2012). Human lesion studies provide converging
evidence that lesions in the right pre-SMA (Floden and Stuss, 2006; Nachev
et al., 2007) and the right inferior frontal gyrus (IFG) subregion pars opercularis im-
pair response inhibition (Aron et al., 2003, 2004, 2014). The first study using TMS
found that temporary deactivation of the right IFG pars opercularis selectively im-
paired the ability to stop an already initiated action, whereas the deactivation of the
same region did not affect physiological arousal or the ability to execute responses,
confirming the important role of the IFG in the regulation of response inhibition
(Chambers et al., 2006). In addition, Cai and colleagues showed that stimulation
of the right pre-SMA slowed the implementation of stopping (measured via SSRT)
but had no influence on modulation of response tendencies and suggested that this
region impairs stopping behavior through a specific disruption of response inhibition
(Cai et al., 2012). These studies are supported by the temporal and spatial precision
afforded by electrocorticography studies, which have found the rIFC responds prior
to successful inhibition (Swann et al., 2009, 2012). Recent studies suggest that this
may reflect a broader role for this region in detecting attentionally salient events
(Hampshire et al., 2010), although it may be the case that in order to evoke right
IFG activity, the salience of these events must be relevant to response control
(Dodds et al., 2011).
Although typically not activated in imaging studies of motor response inhibition,
there is considerable evidence of a role for the orbitofrontal cortex (OFC) in impulse
control. For example, OFC damage in a rodent model increases SSRT (Eagle et al.,
2008), while patients with lesion damage to the OFC show increased self-report and
cognitive measures of impulsivity and altered time perception relative to healthy
controls and non-OFC lesioned patients (Berlin et al., 2004). That said, many
FIGURE 1
Response inhibition on the STOP task produces robust activation in parietal and frontal
cortex, including bilateral inferior frontal gyrus.
3 The neurobiology of control 147
behaviors that appear impulsive might not be driven by a deficit in impulsivity per se.
For example, Torregrossa and colleagues argue that the most robust deficit in OFC-
damaged animals is in reversal learning. Seemingly impulsive behaviors, such as
perseverative responding, and failure to alter responding when rewards for a learned
behavior are devalued, may in fact reflect impairment in the ability to update the
value of an outcome, especially under changing circumstances (Torregrossa
et al., 2008).
There is evidence that regions implicated in motor inhibition and, in particular,
right frontal cortex, are involved in aspects of inhibitory control beyond response
inhibition. This includes the suppression of drug cravings elicited by a cocaine video:
brain activation in the rIFC was increased when inhibiting a craving response and
was negatively coupled with activation levels in the right nucleus accumbens
(Volkow et al., 2010). In a think/no-think paradigm, in which paired associates
are actively suppressed, activation in rIFC was associated with suppressing the sen-
sory components of memories (Depue et al., 2007). de Fockert and colleagues
showed that increasing working memory load increased activity levels in bilateral
inferior and middle frontal gyri while simultaneously increasing the distraction
caused by (and sensory processing of) irrelevant faces (de Fockert et al., 2001).
Hester and colleagues modified this paradigm to show that irrelevant drug stimuli
produced heightened activity in visual cortex in cocaine users relative to drug–naı̈ve
controls (Hester and Garavan, 2009). Critically, those users with the greatest levels
of activity in right prefrontal cortex showed the smallest behavioral interference
caused by the distracting drug stimuli. In a similar manner, a study of the ability
to ignore ecstasy-related stimuli produced greater occipital activation but reduced
right prefrontal activation in ecstasy users relative to controls (Roberts and
Garavan, 2013). Tabibnia and colleagues identified the rIFC in a number of inhib-
itory deficits of methamphetamine-dependent subjects (Tabibnia et al., 2011).
Results indicated lower gray matter in the rIFC in dependent subjects relative to
controls, and gray matter in this region was correlated with drug craving, response
inhibition performance, and a test of affect regulation. Finally, Behan and col-
leagues have recently shown that the rIFC is more active when subjects suppress
reward anticipation (Behan et al., 2015). Here, a novel task required subjects
to prepare for either a target to which they must respond as fast as possible to
receive a reward, or, a stop-signal indicating they should make no response.
A psychophysiological interaction analysis suggested the possibility of having to
inhibit, rather than respond quickly, produced activity increases in the rIFC, which
were correlated with activity decreases in the ventral striatum. Further, the rIFC
activity was adjacent to a distinct rIFC region associated with motor inhibition.
Combined, this brief review suggests that the rIFC may have a broad role in inhib-
itory processes that extend beyond motor inhibition. That said, there remains a lack
of a comprehensive theory relating the similarities and differences between the var-
ious types of inhibitory control to their neurobiological and psychological overlap.
Further research probing the multiple types of inhibitory control in the same sample
may be a valuable advance.
4 RESPONSE INHIBITION AND DRUGS OF ABUSE

Substance using populations are characterized by deficits in response inhibition.
A recent meta-analysis (Smith et al., 2014) of 97 studies found evidence for impaired
response inhibition among those dependent on alcohol, cocaine, methamphetamine,
tobacco, and MDMA.
4.1 NICOTINE
Although findings in the literature are mixed, a recent meta-analysis found a small
but significant effect relating cigarette smoking to response inhibition deficits (Smith
et al., 2014). Results from neuroimaging investigations have generally found alter-
ations in the neural circuitry associated with response inhibition in smokers com-
pared to nonsmoking controls (de Ruiter et al., 2012; Luijten et al., 2013; Nestor
et al., 2011; but see Galván et al., 2011). For example, Nestor et al. (2011) found
that smokers showed reduced activation compared to nonsmokers in a widely distrib-
uted network including the ACC, left IFG, bilateral inferior parietal lobules, and bi-
lateral insula. This is similar to the findings of de Ruiter et al. (2012) who found
reduced activation of the rostral ACC during inhibition in smokers.
One interesting line of research has examined the relationship between neural ac-
tivity during successful response inhibition and craving for cigarettes. Berkman et al.
(2011) demonstrated that subjects with greater task-related neural activity in nodes of
the response inhibition network (bilateral inferior frontal gyrus, SMA, putamen, and
left caudate) smoked less in response to subsequent, naturally occurring occasions of
cigarette craving. These results suggest that functioning in the circuitry underlying
motor inhibition translated to greater behavioral control in response to craving.
Further, these investigators found an inverse relationship between amygdala
activation during response inhibition and behavior, such that subjects with greater
amygdala activation had a stronger positive relationship between craving and smok-
ing behavior. These findings link altered patterns of neural activation with behavioral
constructs known to be critical in addiction. Further, as studies have reported hypo-
activation in the neural circuitry for response inhibition without differences in task
performance, this study underscores the potential utility of neuroimaging as a sen-
sitive measure of neurobiological alterations related to impulsive behavior. Finally,
there is considerable value in studies that link lab-based measures of neurobiological
function with assessments of inhibitory control in the real world. Real-world behav-
iors as assessed, for example, by mobile technologies, open up valuable opportunities
to relate the neurobiology of inhibitory control to avoid drug use in the natural
environment, which in many cases is laden with cues to use.
4.2 ALCOHOL
Alcohol abusers have increased commission error rates compared to nondrinkers or
social drinkers on go/no-go tasks (Kamarajan et al., 2005; Murphy and Garavan,
2011), and longer SSRTs on the stop-signal task compared to controls
4 Response inhibition and drugs of abuse 149
(e.g., Goudriaan et al., 2011; Lawrence et al., 2009; Rubio et al., 2007). However,
mixed results have been reported with a number of studies showing no
difference in response inhibition related to alcohol consumption (Li et al., 2009;
Papachristou et al., 2013; Schmaal et al., 2013). It has been suggested (Smith and
Mattick, 2013) that this may relate to sex differences, based on evidence that heavy
drinking may be preferentially associated with impaired response inhibition in fe-
males (Nederkoorn et al., 2009; Smith and Mattick, 2013; Townshend and Duka,
2005). That said, few studies have been sufficiently powered to specifically examine
sex differences in response inhibition related to alcohol consumption. Nonetheless,
Smith and colleagues reported an overall impairment in response inhibition in their
meta-analysis and suggested that a dose response relationship may exist between im-
paired response inhibition and drinking patterns (Smith et al., 2014). However, there
have been no systematic studies addressing this possibility.
Studies using functional neuroimaging to examine response inhibition in problem
drinkers are limited. Li and colleagues found no performance differences on SSRT
but lower activation in left dlPFC in alcohol-dependent patients (Li et al., 2009).
However, these subjects were all successfully abstinent in alcohol treatment at the
time of scanning, making it difficult to determine if activation patterns were related
to alcohol withdrawal or early recovery from alcohol dependence. Recent findings
have shown that alcohol-use disorders are associated with lower activation in the
IFG, insula, inferior parietal lobule, and ACC compared to controls (Claus et al.,
2013). When comparing heavy to light alcohol consumption in college drinkers,
the heavy drinkers showed impaired performance and altered patterns of neural ac-
tivity during response inhibition in areas including the ACC, portions of the frontal
lobe, hippocampus, and thalamus (Ahmadi et al., 2013). Structural neuroimaging ex-
periments have suggested that chronic alcohol abuse is associated with global vol-
ume reduction, cortical and subcortical gray matter reductions, and enlargement of
the ventricles. The volume loss in frontal, cerebellar, and subcortical regions are be-
lieved to play a critical role in individual differences related to task performance
(Chanraud et al., 2007; Scheurich, 2005; Sullivan, 2003). Therefore, as the neural
architecture supporting response inhibition deteriorates, behavioral inhibition capac-
ity is likely to suffer.
4.3 CANNABIS
Studies in both adolescent and adult cannabis users have found little evidence for
disrupted cognitive performance (Grant et al., 2012; Jager et al., 2010;
Schweinsburg et al., 2010; Tapert et al., 2007); however, see Moreno et al.
(2012). Interestingly, several studies have demonstrated that while there are incon-
sistent effects of cannabis use on inhibitory performance, there are neural differences
that can be detected via fMRI (Behan et al., 2014; Hester et al., 2009; Roberts and
Garavan, 2010; Schweinsburg et al., 2008; Tapert et al., 2007). For example, Roberts
and Garavan investigated neural activity using fMRI during response inhibition
in adolescent cannabis users and nondrug using controls. While users had equal per-
formance to control subjects, the users had increased activation in frontal and parietal
regions during successful inhibitions. This pattern of activation was interpreted to

indicate increased neural resources required of the users to achieve performance
levels comparable to controls (Roberts and Garavan, 2010). Similar results were
found in a study of college students (cannabis users compared to nondrug users)
where there was equal task performance but increased activation in the right inferior
parietal lobule, the right putamen, and the supplementary motor area in the users
(Hester et al., 2009).
It is notable that the pattern of effects in cannabis users (comparable perfor-
mance but greater activation relative to controls) differs from the hypoactivity
associated with other drugs of abuse. Some evidence suggests that heavier use,
earlier onset, and greater cumulative cannabis consumption is associated with
smaller increases in activation in frontal and parietal regions compared to lighter
users or those who begin using later (Schweinsburg et al., 2008, 2010). Such find-
ings indicate that there may be an interaction of brain development and cannabis
exposure on brain function and may additionally suggest a compensatory mecha-
nism in heavy cannabis users (Jacobus et al., 2009). Another possibility is that the
increased activation of cannabis users may compensate for altered functional con-
nectivity between regions. Recently, Orr and colleagues showed increased intrahe-
mispheric and decreased interhemispheric resting-state connectivity in adolescent
heavy cannabis users (Orr et al., 2013). The same sample of adolescent users, when
performing a go/no-go task showed impaired performance but no regional activa-
tion differences relative to controls. Instead, the users showed increased connec-
tivity during the task between bilateral parietal lobes and left cerebellum, and
these same regions showed increased resting-state connectivity (Behan et al.,
2014). Although these results may suggest that atypical patterns of activation in
cannabis users may be related to differences in inter- and intrahemispheric connec-
tivity, the full set of results fails to offer a straightforward message. As cannabis is
the most commonly used illicit drug and the onset of use is common during the
sensitive adolescent neurodevelopmental period, it is important that the effects
of cannabis on neurocognitive function vis-à-vis inhibitory control be the subject
of further inquiry.
4.4 COCAINE
There is strong evidence that cocaine users have poorer response inhibition than
nonusers. This is observed in studies using the stop-signal task (Colzato et al.,
2007; Fillmore and Craig, 2002; Li et al., 2006; Morie et al., 2014; but see
Vonmoos et al., 2013) and in go/no-go tasks (Fernández-Serrano et al., 2011;
Hester and Garavan, 2004; Hester et al., 2007; Kaufman et al., 2003; Lane et al.,
2007). A review by Spronk and colleagues calculated pooled effect sizes for both
SSRT on the stop-signal task and errors of commission on go/no-go tasks and found
a moderate pooled effect size (0.50) of cocaine user status on the stop-signal task
and a moderate to large (0.64) pooled effect size for errors of commission on the
go/no-go task (Spronk et al., 2013). fMRI studies have generally shown reduced
5 Response inhibition and abstinence 151
neural activity in the PFC including rostral ACC and SMA (Hester and Garavan,
2004; Kaufman et al., 2003; Li et al., 2007).
Using independent component analysis on a stop-signal task, Elton and col-
leagues discriminated cocaine users from nonusers based on activity patterns decom-
posed into 11 components. Two of these components were specifically related to
stop-signal success, and cocaine users exhibited decreased activation in these net-
works compared to controls. One network comprised the bilateral IFG, angular gyri,
middle temporal, and posterior parietal gyri, and the other network comprised the
dlPFC, ventrolateral PFC, dorsomedial PFC, anterior insula, and middle temporal
gyrus (Elton et al., 2014).
4.5 MDMA/ECSTASY
A meta-analysis found that overall there is a small effect size on inhibitory errors in
heavy MDMA users compared to controls (Smith et al., 2014). Among individual
studies, there are several that reported no behavioral performance differences
(von Geusau et al. 2004; Quednow et al., 2006; Roberts et al., 2013; Roberts and
Garavan, 2010). However, two of these studies used neuroimaging and found altered
neural processing in MDMA users. For example, Roberts and colleagues found that
ecstasy/polydrug users showed altered EEG patterns suggestive of attentional or in-
hibitory deficits (Roberts et al., 2013). Similarly, Roberts and Garavan (2010) found
intact performance but increased activation in the response inhibition network (right
DLPFC, inferior frontal gyrus, and parietal lobule) in recreational ecstasy users.
Other studies of current MDMA users have reported moderately impaired behavioral
performance in response inhibition (Hoshi et al., 2007). Taken together, the available
literature suggests a small impairment in response inhibition associated with MDMA
use and altered neural processing in users with intact behavioral performance.
5 RESPONSE INHIBITION AND ABSTINENCE

Relapse is, in many regards, a defining characteristic of drug dependence. Successful
abstinence might be viewed within a framework whereby prefrontal cognitive sys-
tems seek to control biased attention and pathological behaviors. Hence, successful
abstinence may rest on the outcome of the antagonism between drug-wanting sys-
tems driven, for example, by ventral striatally mediated salience attribution systems
(Robinson and Berridge, 2003), and drug-denying systems governed by the prefron-
tal cortex (Goldstein and Volkow, 2002; Fig. 2).
There is, however, relatively little empirical data on the neurobiology of success-
ful abstinence despite its potential value for informing therapeutic interventions. The
extant literature has typically investigated short-term abstinence and has revealed
many persistent deficits, which, for example, for cocaine users, are more pronounced
in heavy users in lateral and medial prefrontal regions associated with cognitive
control (Bolla et al., 2003, 2004). Abstinent cannabis users show a similar pattern
FIGURE 2
We hypothesize that abstinence relies upon recovery of prefrontal systems involved in
inhibitory control (regions such as the right IFG and OFC shown on the left). Vulnerability
to relapse may be reflected in reinforcement or salience systems (involving regions such
as the ventral striatum shown on the right). We hypothesize that relapse may arise from
lapses in the prefrontal regulatory systems.
of lateral and medial hypoactivity but have also been reported to show bilateral hip-
pocampal hyperactivity (Eldreth et al., 2004). There is, however, evidence to suggest
that prolonged abstinence will correct the general pattern of prefrontal hypoactivity
in users (see below) with, for example, cocaine abstinence reducing high-risk re-
sponses on a gambling task (Bartzokis et al., 2000). Structural MRI studies have
found reduced gray matter volume in prefrontal, orbitofrontal, and cingulate regions
in cocaine abstinent individuals (Fein et al., 2002; Matochik et al., 2003), which,
some argue, can last even with prolonged abstinence (Tanabe et al., 2009). Interest-
ingly, Connolly and colleagues found in a cross-sectional analysis that cocaine ab-
stinent individuals reached control-like levels of gray matter volumes in the
cingulate, insula, and dlPFC by 35 weeks of abstinence (Connolly et al., 2013).
During abstinence, impulse control might be important for suppressing drug-
seeking behaviors and drug cravings. Although subjective reports of craving often
prove to be poor predictors of subsequent abstinence, cognitive and neuroimaging
measures can sometimes do better (Grüsser et al., 2004; Kosten et al., 2005). For
example, higher scores on a self-report measure of impulsivity (the Barratt Impul-
siveness Scale) have been shown to predict poorer treatment outcome (Moeller
et al., 2001; Patkar et al., 2004). With regard to brain predictors, unfortunately,
the neuroimaging literature on predicting relapse is small and has employed a variety
of tasks that were not necessarily designed to induce a craving response or to assess
the user’s ability to exercise inhibitory control over that response. Nonetheless, the
existing results do identify prefrontal systems, among other regions, as effective pre-
dictors of treatment outcome. For example, using a two-button prediction task, Pau-
lus and colleagues showed activation levels in prefrontal, temporal, and posterior
cingulate regions early in abstinence to predict subsequent relapse for methamphet-
amine users (Paulus et al., 2005). Grüsser et al. (2004) found that activity in response
to alcohol-related stimuli in the putamen, ACC, and medial prefrontal cortex
5 Response inhibition and abstinence 153
predicted relapse. In cocaine treatment-seeking individuals, fMRI error-related pro-

cessing (stop-error vs. stop-success) revealed blunted activity in the dorsal ACC pre-
dicted relapse in both sexes, while females exhibited reduced thalamic activity, and
males exhibited reduced insular activity (Luo et al., 2013). Although it does not fol-
low from these findings that behavioral measures of impulse control should also pre-
dict abstinence, the predictive value of prefrontal cortex suggests that regulatory
processes may be involved.
Given the important role that cognitive processes may play in avoiding relapse in
drug users and gamblers (Cox et al., 2002; Goudriaan et al., 2008; Passetti et al.,
2008; Waters et al., 2003), it may be the case that the best predictors of treatment
outcome are those that reflect cognitive control over drug urges rather than the drug
urges themselves. This is supported by a study by Brewer et al. (2008) who identified
cognitive control prefrontal regions, in addition to other subcortical and posterior
cingulate regions, as being the best predictors of treatment outcome in a
treatment-receiving sample of cocaine users. Further evidence for the assertion that
impulse control might contribute to successful abstinence arises from cross-sectional
research of abstinent former users using a go/no-go task. These studies show an ap-
parent reversal in activation patterns, such that prefrontal hypoactivity in current
users is paired with prefrontal hyperactivity in abstinent users. For example,
Connolly et al. (2012) showed that both short-term abstinent cocaine users (1–5
weeks) and long-term abstinent users (4–24 months) present with fMRI hyperactivity
in cognitive control regions relative to drug–naı̈ve controls. That is, the brain regions
involved in impulse control (e.g., right middle and rIFC), which are consistently
shown to be hypoactive in current users, show elevated activity in former users com-
pared to drug–naı̈ve controls. Subsequent studies have shown former users to be
either comparable in performance, fMRI activation levels, and motor-inhibition-
related ERP components to controls (Bell et al., 2014; Morie et al., 2014) or to show
elevated activation associated with successful inhibitions (Hester et al., 2013). The
latter study also revealed blunted activation in response to errors and punishments in
the former users suggesting some deficits may persist longer into abstinence.
Evidence for enhanced cognitive control contributing to successful abstinence is
also observed in former cigarette smokers (abstinent for 2 years). Using a go/no-go
task, current smokers showed reduced activity relative to controls in the dlPFC and
the ACC while the former smokers revealed greater inhibition- and error-related ac-
tivation in the ACC relative to the current smokers (Nestor et al., 2011). A recent
study in cigarette smokers highlighted behavioral effects of practicing self-control
(i.e., small acts of impulse control such as avoiding sweets were practiced over 2
weeks before quitting) which significantly improved abstinence rates; 27% in the
self-control group, relative to 12% in a control condition, were still abstinent 1 month
after quitting (Muraven, 2010).
TMS and tDCS have shown some efficacy in enhancing cognitive control. Jacob-
son and colleagues demonstrated faster SSRTs while stimulating the right inferior
frontal gyrus (Jacobson et al., 2011). Applying this technique to substance-abusing
individuals may prove fruitful. One study in alcohol detoxification found a single
session of TMS over the rIFC facilitated cognitive control performance a week later
(Herremans et al., 2013). Similarly, pharmacological interventions targeting
cognitive enhancement in cigarette smokers have provided some support for the
facilitation of abstinence. Focusing on studies directly assessing response inhibition
performance, galantamine, a cholinesterase inhibitor, has reduced subjective
craving for cigarettes, while improving performance on a go/no-go task (Sofuoglu
et al., 2012). Another study suggests that the use of an NMDA partial agonist,
D-cylcoserine, attenuates subjective ratings of cigarette “stimulation” and
“relaxation,” while improving performance on a go/no-go task (Nesic et al.,
2011). Lastly, in a combined fMRI-pharmacological study of guanfacine, a norad-
renergic agonist, smokers exhibited reduced cigarette consumption. While no effect
was found on task performance, the fMRI results indicate guanfacine attenuated
dlPFC responses. The authors interpret this finding as a possible guanfacine-related
facilitation of cognitive efficiency.
In summary, the extant literature suggests compromised inhibitory control in ac-
tive users and normalized or enhanced control in abstinent users. If inhibitory control
is shown to be an important contributor to abstinence then this raises exciting pos-
sibilities for pharmacological or behavioral interventions. In time, neuroimaging
measures may enable us to predict who is most likely to abstain (e.g., related to
the integrity of the circuitry underlying inhibitory control) and, by tracking recovery
in this circuitry, give guidance on who is most at risk for subsequent relapse.

The preceding review suggests that deficits in inhibitory control characterize sub-
stance dependence. There are, however, drug-specific effects that require further
elaboration (e.g., the mixed findings in cannabis users). The integration of functional
activation, functional connectivity, and brain structural data is important, but so too
is a much richer phenotypic characterization of the users including their drug use
histories (age of onset, polydrug use), mental health comorbidities, family and en-
vironmental influences, and so on. In reviewing the literature, there persists a lack
of a comprehensive understanding on how the various types of inhibitory control re-
late to one another, psychologically and neurobiologically. More assessments of
drug use and other types of inhibitory control (e.g., delaying gratification) or inhib-
itory control in reward-related contexts may yield new insights. It is a conundrum
that although different aspects of inhibitory control appear to be uncorrelated with
one another (e.g., self-report personality measures, impulsive choice, and impulsive
responding; Reynolds et al., 2006), drug users score highly impulsive on all. Com-
bining this with the evidence that inhibitory control is related to reward processes
such as drug-induced euphoria and drug self-administration (Cervantes et al.,
2013; Weafer and de Wit, 2013), suggests that more conceptual work is required
to integrate these constructs. Finally, as noted above, relating lab-based measures
References 155
of inhibitory control to drug urges and craving in the natural environment is an im-
portant extension of the existing research.
With regard to abstinence, there are two questions of primary importance, and for
both, inhibitory control appears to be a central construct. First, to what extent does
inhibitory control predicts abstinence? This is important clinically (i.e., identifying
who is most likely to relapse can help in allocating interventions and additional ser-
vices) and also theoretically (i.e., the predictors of relapse give good guidance on the
mechanisms that may contribute in a causal manner to abstinence; Garavan et al.,
2013). Second, what is the time-course of recovery of inhibitory control and other
processes pertinent to addiction? One speculation is that certain processes (e.g.,
the incentive salience attributed to drugs and drug cues mediated by structures such
as the ventral striatum) may persist long after the cessation of use and may underlie
relapse risk. It may be the case that inhibitory control recovers to normal (or greater
than normal) levels relatively early in abstinence, and while inhibitory control exer-
cised over drug cravings and behaviors is essential to abstinence, relapse is highly
likely when this regulatory function becomes disrupted as happens, for example, un-
der stressful situations. Large sample, longitudinal studies of abstainers that assess
multiple functions at multiple time-points are required to fully elaborate the role that
inhibitory control contributes to avoiding relapse.
REFERENCES
Ahmadi, A., Pearlson, G.D., Meda, S.A., Dager, A., Potenza, M.N., Rosen, R., Austad, C.S.,
et al., 2013. Influence of alcohol use on neural response to go/no-go task in college
drinkers. Neuropsychopharmacology 38 (11), 2197–2208. http://dx.doi.org/10.1038/
npp.2013.119.
Aron, A.R., Poldrack, R.A., 2006. Cortical and subcortical contributions to stop signal re-
sponse inhibition: role of the subthalamic nucleus. J. Neurosci. 26 (9), 2424–2433.
http://dx.doi.org/10.1523/JNEUROSCI.4682-05.2006.
Aron, A.R., Fletcher, P.C., Bullmore, E.T., Sahakian, B.J., Robbins, T.W., 2003. Stop-signal
inhibition disrupted by damage to right inferior frontal gyrus in humans. Nat. Neurosci.
6 (2), 115–116. http://dx.doi.org/10.1038/nn1003.
Aron, A.R., Robbins, T.W., Poldrack, R.A., 2004. Inhibition and the right inferior frontal cor-
tex. Trends Cogn. Sci. 8 (4), 170–177. http://dx.doi.org/10.1016/j.tics.2004.02.010.
tex: one decade on. Trends Cogn. Sci. 18 (4), 177–185. http://dx.doi.org/10.1016/j.
tics.2013.12.003.
Atkinson, R.C., Shiffrin, R.M., 1968. Human Memory: A Proposed System and Its Control
Processes. Academic Press, Oxford, England. xi, 249, http://search.proquest.com/psy
cinfo/docview/615905557/24D0F579AE654572PQ/1?accountid¼14679.
Badre, D., Wagner, A.D., 2006. Computational and neurobiological mechanisms underlying
cognitive flexibility. Proc. Natl. Acad. Sci. U. S. A. 103 (18), 7186–7191. http://dx.doi.
org/10.1073/pnas.0509550103.
Bartzokis, G., Lu, P.H., Beckson, M., Rapoport, R., Grant, S., Wiseman, E.J., London, E.D.,
2000. Abstinence from cocaine reduces high-risk responses on a gambling task.
Neuropsychopharmacology 22 (1), 102–103. http://dx.doi.org/10.1016/S0893-133X(99)

00077-9.
neurocognitive perspective. Nat. Neurosci. 8 (11), 1458–1463. http://dx.doi.org/10.1038/
nn1584.
Behan, B., Connolly, C.G., Datwani, S., Doucet, M., Ivanovic, J., Morioka, R., Stone, A.,
Watts, R., Smyth, B., Garavan, H., 2014. Response inhibition and elevated parietal-
cerebellar correlations in chronic adolescent cannabis users. Neuropharmacology
84, 131–137. http://dx.doi.org/10.1016/j.neuropharm.2013.05.027.
Behan, B., Stone, A., Garavan, H., 2015. Right prefrontal and ventral striatum interactions
underlying impulsive choice and impulsive responding. Hum. Brain Mapp. 36 (1),
187–198. http://dx.doi.org/10.1002/hbm.22621.
Bell, R.P., Foxe, J.J., Ross, L.A., Garavan, H., 2014. Intact inhibitory control processes in ab-
stinent drug abusers (I): a functional neuroimaging study in former cocaine addicts.
Neuropharmacology 82, 143–150. http://dx.doi.org/10.1016/j.neuropharm.2013.02.018.
Berkman, E.T., Falk, E.B., Lieberman, M.D., 2011. In the trenches of real-world self-control
neural correlates of breaking the link between craving and smoking. Psychol. Sci. 22 (4),
498–506. http://dx.doi.org/10.1177/0956797611400918.
Berlin, H.A., Rolls, E.T., Kischka, U., 2004. Impulsivity, time perception, emotion and rein-
forcement sensitivity in patients with orbitofrontal cortex lesions. Brain 127 (5),
1108–1126. http://dx.doi.org/10.1093/brain/awh135.
Bolla, K.I., Eldreth, D.A., London, E.D., Kiehl, K.A., Mouratidis, M., Contoreggi, C.,
Matochik, J.A., et al., 2003. Orbitofrontal cortex dysfunction in abstinent cocaine abusers
performing a decision-making task. Neuroimage 19 (3), 1085–1094.
Bolla, K.I., Ernst, M., Kiehl, K., Mouratidis, M., Eldreth, D., Contoreggi, C., Matochik, J.,
et al., 2004. Prefrontal cortical dysfunction in abstinent cocaine abusers.
J. Neuropsychiatry Clin. Neurosci. 16 (4), 456–464. http://dx.doi.org/10.1176/appi.
neuropsych.16.4.456.
Brewer, J.A., Worhunsky, P.D., Carroll, K.M., Rounsaville, B.J., Potenza, M.N., 2008. Pre-
treatment brain activation during stroop task is associated with outcomes in cocaine-
dependent patients. Biol. Psychiatry 64 (11), 998–1004. http://dx.doi.org/10.1016/j.
biopsych.2008.05.024.
Cai, W., George, J.S., Verbruggen, F., Chambers, C.D., Aron, A.R., 2012. The role of the right
presupplementary motor area in stopping action: two studies with event-related transcra-
nial magnetic stimulation. J. Neurophysiol. 108 (2), 380–389. http://dx.doi.org/10.1152/
jn.00132.2012.
Cervantes, M.C., Laughlin, R.E., David Jentsch, J., 2013. Cocaine self-administration behav-
ior in inbred mouse lines segregating different capacities for inhibitory control. Psycho-
pharmacology (Berl) 229 (3), 515–525. http://dx.doi.org/10.1007/s00213-013-3135-4.
Chambers, C.D., Bellgrove, M.A., Stokes, M.G., Henderson, T.R., Garavan, H., Robertson, I.H.,
Morris, A.P., Mattingley, J.B., 2006. Executive ‘brake failure’ following deactivation
of human frontal lobe. J. Cogn. Neurosci. 18 (3), 444–455. http://dx.doi.org/
10.1162/089892906775990606.
Chanraud, S., Martelli, C., Delain, F., Kostogianni, N., Douaud, G., Aubin, H.-J.,
Reynaud, M., Martinot, J.-L., 2007. Brain morphometry and cognitive performance
in detoxified alcohol-dependents with preserved psychosocial functioning.
Neuropsychopharmacology 32 (2), 429–438. http://dx.doi.org/10.1038/sj.npp.1301219.
References 157
Claus, E.D., Feldstein Ewing, S.W., Filbey, F.M., Hutchison, K.E., 2013. Behavioral control
in alcohol use disorders: relationships with severity. J. Stud. Alcohol Drugs 74 (1),
141–151.
Colzato, L.S., van den Wildenberg, W.P., Hommel, B., 2007. Impaired inhibitory control in
recreational cocaine users. PLoS One 2 (11), e1143. http://dx.doi.org/10.1371/journal.
pone.0001143.
Connolly, C.G., Foxe, J.J., Nierenberg, J., Shpaner, M., Garavan, H., 2012. The neurobiology
of cognitive control in successful cocaine abstinence. Drug Alcohol Depend. 121 (1–2),
45–53. http://dx.doi.org/10.1016/j.drugalcdep.2011.08.007.
Connolly, C.G., Bell, R.P., Foxe, J.J., Garavan, H., 2013. Dissociated grey matter changes with
prolonged addiction and extended abstinence in cocaine users. PLoS One 8 (3), e59645.
http://dx.doi.org/10.1371/journal.pone.0059645.
Cox, W.M., Hogan, L.M., Kristian, M.R., Race, J.H., 2002. Alcohol attentional bias as a pre-
dictor of alcohol abusers’ treatment outcome. Drug Alcohol Depend. 68 (3), 237–243.
http://dx.doi.org/10.1016/S0376-8716(02)00219-3.
D’Esposito, M., Detre, J.A., Alsop, D.C., Shin, R.K., Atlas, S., Grossman, M., 1995. The neu-
ral basis of the central executive system of working memory. Nature 378 (6554), 279–281.
http://dx.doi.org/10.1038/378279a0.
de Fockert, J.W., Rees, G., Frith, C.D., Lavie, N., 2001. The role of working memory in
visual selective attention. Science 291 (5509), 1803–1806. http://dx.doi.org/10.1126/
science.1056496.
Depue, B.E., Curran, T., Banich, M.T., 2007. Prefrontal regions orchestrate suppression of
emotional memories via a two-phase process. Science 317 (5835), 215–219. http://dx.
doi.org/10.1126/science.1139560.
Dodds, C.M., Morein-Zamir, S., Robbins, T.W., 2011. Dissociating inhibition, attention,
and response control in the frontoparietal network using functional magnetic resonance
imaging. Cereb. Cortex 21 (5), 1155–1165. http://dx.doi.org/10.1093/cercor/bhq187.
Dosenbach, N.U., Fair, D.A., Miezin, F.M., Cohen, A.L., Wenger, K.K., Dosenbach, R.A.,
Fox, M.D., et al., 2007. Distinct brain networks for adaptive and stable task control in
humans. Proc. Natl. Acad. Sci. 104 (26), 11073–11078. http://dx.doi.org/10.1073/
pnas.0704320104.
Dove, A., Pollmann, S., Schubert, T., Wiggins, C.J., von Cramon, D.Y., 2000. Prefrontal cor-
tex activation in task switching: an event-related fMRI study. Cogn. Brain Res. 9 (1),
103–109. http://dx.doi.org/10.1016/S0926-6410(99)00029-4.
Duann, J.-R., Ide, J.S., Luo, X., Li, C.-s.R., 2009. Functional connectivity delineates distinct
roles of the inferior frontal cortex and presupplementary motor area in stop signal inhibi-
tion. J. Neurosci. 29 (32), 10171–10179. http://dx.doi.org/10.1523/JNEUROSCI.1300-
09.2009.
Eagle, D.M., Baunez, C., Hutcheson, D.M., Lehmann, O., Shah, A.P., Robbins, T.W., 2008.
Stop-signal reaction-time task performance: role of prefrontal cortex and subthalamic
nucleus. Cereb. Cortex 18 (1), 178–188. http://dx.doi.org/10.1093/cercor/bhm044.
Edin, F., Klingberg, T., Johansson, P., McNab, F., Tegnér, J., Compte, A., 2009. Mechanism
for top-down control of working memory capacity. Proc. Natl. Acad. Sci. 106 (16),
6802–6807. http://dx.doi.org/10.1073/pnas.0901894106.
Eldreth, D.A., Matochik, J.A., Cadet, J.L., Bolla, K.I., 2004. Abnormal brain activity in
prefrontal brain regions in abstinent marijuana users. Neuroimage 23 (3), 914–920.
http://dx.doi.org/10.1016/j.neuroimage.2004.07.032.
Elton, A., Young, J., Smitherman, S., Gross, R.E., Mletzko, T., Kilts, C.D., 2014. Neural net-
work activation during a stop-signal task discriminates cocaine-dependent from non-drug-
abusing men. Addict. Biol. 19 (3), 427–438. http://dx.doi.org/10.1111/adb.12011.
Fein, G., Di Sclafani, V., Meyerhoff, D.J., 2002. Prefrontal cortical volume reduction associ-
ated with frontal cortex function deficit in 6-week abstinent crack-cocaine dependent men.
Drug Alcohol Depend. 68 (1), 87–93.
Fernández-Serrano, M.J., Perales, J.C., Moreno-López, L., Pérez-Garcı́a, M., Verdejo-Garcı́a,
A., 2011. Neuropsychological profiling of impulsivity and compulsivity in cocaine depen-
dent individuals. Psychopharmacology (Berl) 219 (2), 673–683. http://dx.doi.org/10.1007/
s00213-011-2485-z.
Fillmore, M.T., Craig, R.R., 2002. Impaired inhibitory control of behavior in chronic cocaine
users. Drug Alcohol Depend. 66 (3), 265–273. http://dx.doi.org/10.1016/S0376-8716(01)
00206-X.
Floden, D., Stuss, D.T., 2006. Inhibitory control is slowed in patients with right superior me-
dial frontal damage. J. Cogn. Neurosci. 18 (11), 1843–1849. http://dx.doi.org/10.1162/
jocn.2006.18.11.1843.
Forman, S.D., Dougherty, G.G., Casey, B.J., Siegle, G.J., Braver, T.S., Barch, D.M.,
Stenger, V.A., Wick-Hull, C., Pisarov, L.A., Lorensen, E., 2004. Opiate addicts lack
error-dependent activation of rostral anterior cingulate. Biol. Psychiatry 55 (5),
531–537. http://dx.doi.org/10.1016/j.biopsych.2003.09.011.
Galván, A., Poldrack, R.A., Baker, C.M., McGlennen, K.M., London, E.D., 2011. Neural cor-
relates of response inhibition and cigarette smoking in late adolescence.
Neuropsychopharmacology 36 (5), 970–978. http://dx.doi.org/10.1038/npp.2010.235.
Garavan, H., Ross, T.J., Stein, E.A., 1999. Right hemispheric dominance of inhibitory control:
an event-related functional MRI study. Proc. Natl. Acad. Sci. 96 (14), 8301–8306. http://
dx.doi.org/10.1073/pnas.96.14.8301.
Garavan, H., Hester, R., Murphy, K., Fassbender, C., Kelly, C., 2006. Individual differences in
the functional neuroanatomy of inhibitory control. Brain Res. 1105 (1), 130–142. http://dx.
doi.org/10.1016/j.brainres.2006.03.029.
Garavan, H., Brennan, K.L., Hester, R., Whelan, R., 2013. The neurobiology of successful
abstinence. Curr. Opin. Neurobiol. 23 (4), 668–674. http://dx.doi.org/10.1016/j.
conb.2013.01.029.
Goldstein, R.Z., Volkow, N.D., 2002. Drug addiction and its underlying neurobiological basis:
neuroimaging evidence for the involvement of the frontal cortex. Am. J. Psychiatr.
159 (10), 1642–1652. http://dx.doi.org/10.1176/appi.ajp.159.10.1642.
Goudriaan, A.E., Oosterlaan, J., De Beurs, E., Van Den Brink, W., 2008. The role of self-
reported impulsivity and reward sensitivity versus neurocognitive measures of disinhibi-
tion and decision-making in the prediction of relapse in pathological gamblers. Psychol.
Med. 38 (01), 41–50. http://dx.doi.org/10.1017/S0033291707000694.
Goudriaan, A.E., Grekin, E.R., Sher, K.J., 2011. Decision making and response inhibition as
predictors of heavy alcohol use: a prospective study. Alcohol. Clin. Exp. Res. 35 (6),
1050–1057. http://dx.doi.org/10.1111/j.1530-0277.2011.01437.x.
Grant, S., London, E.D., Newlin, D.B., Villemagne, V.L., Liu, X., Contoreggi, C., Phillips, R.L.,
Kimes, A.S., Margolin, A., 1996. Activation of memory circuits during cue-elicited cocaine
craving. Proc. Natl. Acad. Sci. 93 (21), 12040–12045.
Grant, J.E., Chamberlain, S.R., Schreiber, L., Odlaug, B.L., 2012. Neuropsychological deficits
associated with cannabis use in young adults. Drug Alcohol Depend. 121 (1–2), 159–162.
http://dx.doi.org/10.1016/j.drugalcdep.2011.08.015.
References 159
Grüsser, S.M., Wrase, J., Klein, S., Hermann, D., Smolka, M.N., Ruf, M., Weber-Fahr, W.,
et al., 2004. Cue-induced activation of the striatum and medial prefrontal cortex is
associated with subsequent relapse in abstinent alcoholics. Psychopharmacology (Berl)
175 (3), 296–302. http://dx.doi.org/10.1007/s00213-004-1828-4.
Hampshire, A., Chamberlain, S.R., Monti, M.M., Duncan, J., Owen, A.M., 2010. The role of
the right inferior frontal gyrus: inhibition and attentional control. Neuroimage 50 (3),
1313–1319. http://dx.doi.org/10.1016/j.neuroimage.2009.12.109.
Herremans, S.C., Vanderhasselt, M.-A., De Raedt, R., Baeken, C., 2013. Reduced intra-
individual reaction time variability during a Go–NoGo task in detoxified alcohol-
dependent patients after one right-sided dorsolateral prefrontal HF-rTMS session. Alcohol
Alcohol. 48 (5), 552–557. http://dx.doi.org/10.1093/alcalc/agt054.
Hester, R., Garavan, H., 2004. Executive dysfunction in cocaine addiction: evidence for dis-
cordant frontal, cingulate, and cerebellar activity. J. Neurosci. 24 (49), 11017–11022.
http://dx.doi.org/10.1523/JNEUROSCI.3321-04.2004.
Hester, R., Garavan, H., 2009. Neural mechanisms underlying drug-related cue distraction in
active cocaine users. Pharmacol. Biochem. Behav. 93 (3), 270–277. http://dx.doi.org/
10.1016/j.pbb.2008.12.009.
Hester, R., Dixon, V., Garavan, H., 2006. A consistent attentional bias for drug-related
material in active cocaine users across word and picture versions of the emotional
Stroop task. Drug Alcohol Depend. 81 (3), 251–257. http://dx.doi.org/10.1016/j.
drugalcdep.2005.07.002.
Hester, R., Simões-Franklin, C., Garavan, H., 2007. Post-error behavior in active
cocaine users: poor awareness of errors in the presence of intact performance adjust-
ments. Neuropsychopharmacology 32 (9), 1974–1984. http://dx.doi.org/10.1038/sj.
npp.1301326.
Hester, R., Nestor, L., Garavan, H., 2009. Impaired error awareness and anterior cingulate cor-
tex hypoactivity in chronic cannabis users. Neuropsychopharmacology 34 (11),
2450–2458. http://dx.doi.org/10.1038/npp.2009.67.
Hester, R., Bell, R.P., Foxe, J.J., Garavan, H., 2013. The influence of monetary punishment on
cognitive control in abstinent cocaine-users. Drug Alcohol Depend. 133 (1), 86–93. http://
dx.doi.org/10.1016/j.drugalcdep.2013.05.027.
Hoshi, R., Mullins, K., Boundy, C., Brignell, C., Piccini, P., Curran, H.V., 2007. Neurocog-
nitive function in current and ex-users of ecstasy in comparison to both matched polydrug-
using controls and drug-naive controls. Psychopharmacology 194 (3), 371–379.
Jacobson, L., Javitt, D.C., Lavidor, M., 2011. Activation of inhibition: diminishing impulsive
behavior by direct current stimulation over the inferior frontal gyrus. J. Cogn. Neurosci.
23 (11), 3380–3387. http://dx.doi.org/10.1162/jocn_a_00020.
Jacobus, J., Bava, S., Cohen-Zion, M., Mahmood, O., Tapert, S.F., 2009. Functional conse-
quences of marijuana use in adolescents. Pharmacol. Biochem. Behav. 92 (4), 559–565.
http://dx.doi.org/10.1016/j.pbb.2009.04.001.
Jager, G., Block, R.I., Luijten, M., Ramsey, N.F., 2010. Cannabis use and memory brain func-
tion in adolescent boys: a cross-sectional multicenter functional magnetic resonance im-
aging study. J. Am. Acad. Child Adolesc. Psychiatry 49 (6). http://dx.doi.org/10.1016/j.
jaac.2010.02.001. 561–72.e3.
Kamarajan, C., Porjesz, B., Jones, K.A., Choi, K., Chorlian, D.B., Padmanabhapillai, A.,
Rangaswamy, M., Stimus, A.T., Begleiter, H., 2005. Alcoholism is a disinhibitory
disorder: neurophysiological evidence from a Go/No-Go task. Biol. Psychol. 69 (3),
353–373. http://dx.doi.org/10.1016/j.biopsycho.2004.08.004.
Kaufman, J.N., Ross, T.J., Stein, E.A., Garavan, H., 2003. Cingulate hypoactivity in cocaine
users during a GO-NOGO task as revealed by event-related functional magnetic resonance
imaging. J. Neurosci. 23 (21), 7839–7843.
Kim, C., Chung, C., Kim, J., 2013. Task-dependent response conflict monitoring and cognitive
control in anterior cingulate and dorsolateral prefrontal cortices. Brain Res.
1537, 216–223. http://dx.doi.org/10.1016/j.brainres.2013.08.055.
Kosten, T.R., Scanley, B.E., Tucker, K.A., Oliveto, A., Prince, C., Sinha, R., Potenza, M.N.,
Skudlarski, P., Wexler, B.E., 2005. Cue-induced brain activity changes and relapse in
cocaine-dependent patients. Neuropsychopharmacology 31 (3), 644–650. http://dx.doi.
org/10.1038/sj.npp.1300851.
Lane, S.D., Gerard Moeller, F., Steinberg, J.L., Buzby, M., Kosten, T.R., 2007. Performance of
cocaine dependent individuals and controls on a response inhibition task with varying
levels of difficulty. Am. J. Drug Alcohol Abuse 33 (5), 717–726. http://dx.doi.org/
10.1080/00952990701522724.
Lawrence, A.J., Luty, J., Bogdan, N.A., Sahakian, B.J., Clark, L., 2009. Impulsivity and re-
sponse inhibition in alcohol dependence and problem gambling. Psychopharmacology
(Berl) 207 (1), 163–172. http://dx.doi.org/10.1007/s00213-009-1645-x.
Lhermitte, F., 1986. Human autonomy and the frontal lobes. Part II: patient behavior in com-
plex and social situations: the ‘environmental dependency syndrome’. Ann. Neurol. 19 (4),
335–343. http://dx.doi.org/10.1002/ana.410190405.
Li, C.-s.R., Milivojevic, V., Kemp, K., Hong, K., Sinha, R., 2006. Performance monitoring and
stop signal inhibition in abstinent patients with cocaine dependence. Drug Alcohol De-
pend. 85 (3), 205–212. http://dx.doi.org/10.1016/j.drugalcdep.2006.04.008.
Li, C.-s.R., Huang, C., Yan, P., Bhagwagar, Z., Milivojevic, V., Sinha, R., 2007. Neural
correlates of impulse control during stop signal inhibition in cocaine-dependent Men.
Neuropsychopharmacology 33 (8), 1798–1806. http://dx.doi.org/10.1038/sj.npp.1301568.
Li, C.-s.R., Luo, X., Yan, P., Bergquist, K., Sinha, R., 2009. Altered impulse control in alcohol
dependence: neural measures of stop signal performance. Alcohol. Clin. Exp. Res. 33 (4),
Logan, G.D., Cowan, W.B., 1984. On the ability to inhibit thought and action: a theory of an act
of control. Psychol. Rev. 91 (3), 295–327. http://dx.doi.org/10.1037/0033-295X.91.3.295.
Luijten, M., O’Connor, D.A., Rossiter, S., Franken, I.H., Hester, R., 2013. Effects of reward
and punishment on brain activations associated with inhibitory control in cigarette
smokers. Addiction 108 (11), 1969–1978. http://dx.doi.org/10.1111/add.12276.
Luijten, M., Machielsen, M.W.J., Veltman, D.J., Hester, R., de Haan, L., Franken, I.H.A.,
2014. Systematic review of ERP and fMRI studies investigating inhibitory control and er-
ror processing in people with substance dependence and behavioural addictions.
J. Psychiatry Neurosci. 39 (3), 149–169. http://dx.doi.org/10.1503/jpn.130052.
Luo, X., Zhang, S., Hu, S., Bednarski, S.R., Erdman, E., Farr, O.M., Hong, K.-I., Sinha, R.,
Mazure, C.M., Chiang-Shan, R.L., 2013. Error processing and gender-shared and -specific
neural predictors of relapse in cocaine dependence. Brain 136 (Pt. 4), 1231–1244. http://
dx.doi.org/10.1093/brain/awt040.
Luria, A.R., Pribram, K.H., 1973. The frontal lobes and the regulation of behavior.
Academic Press, Oxford, England. xii, 332, http://search.proquest.com/psycinfo/docv
iew/615922321/809F37D77359444DPQ/1?accountid¼14679.
Mansouri, F.A., Tanaka, K., Buckley, M.J., 2009. Conflict-induced behavioural adjustment: a
clue to the executive functions of the prefrontal cortex. Nat. Rev. Neurosci. 10 (2),
141–152. http://dx.doi.org/10.1038/nrn2538.
References 161
Matochik, J.A., London, E.D., Eldreth, D.A., Cadet, J.-L., Bolla, K.I., 2003. Frontal cortical
tissue composition in abstinent cocaine abusers: a magnetic resonance imaging study.
Neuroimage 19 (3), 1095–1102. http://dx.doi.org/10.1016/S1053-8119(03)00244-1.
Moeller, F.G., Dougherty, D.M., Barratt, E.S., Schmitz, J.M., Swann, A.C., Grabowski, J.,
2001. The impact of impulsivity on cocaine use and retention in treatment. J. Subst. Abuse
Treat. 21 (4), 193–198. http://dx.doi.org/10.1016/S0740-5472(01)00202-1.
Moreno, M., Estevez, A.F., Zaldivar, F., Montes, J.M.G., Gutiérrez-Ferre, V.E., Esteban, L.,
Sánchez-Santed, F., Flores, P., 2012. Impulsivity differences in recreational cannabis users
and binge drinkers in a university population. Drug Alcohol Depend. 124 (3), 355–362.
Morie, K.P., De Sanctis, P., Garavan, H., Foxe, J.J., 2014. Executive dysfunction and reward
dysregulation: a high-density electrical mapping study in cocaine abusers.
Neuropharmacology 85, 397–407. http://dx.doi.org/10.1016/j.neuropharm.2014.05.016.
Muraven, M., 2010. Practicing self-control lowers the risk of smoking lapse. Psychol. Addict.
Behav. 24 (3), 446–452. http://dx.doi.org/10.1037/a0018545.
Murphy, P., Garavan, H., 2011. Cognitive predictors of problem drinking and AUDIT scores
among college students. Drug Alcohol Depend. 115 (1–2), 94–100. http://dx.doi.org/
10.1016/j.drugalcdep.2010.10.011.
Nachev, P., Wydell, H., O’Neill, K., Husain, M., Kennard, C., 2007. The role of the pre-
supplementary motor area in the control of action. Neuroimage 36, T155–T163. http://
dx.doi.org/10.1016/j.neuroimage.2007.03.034.
Nederkoorn, C., Baltus, M., Guerrieri, R., Wiers, R.W., 2009. Heavy drinking is associated
with deficient response inhibition in women but not in men. Pharmacol. Biochem. Behav.
93 (3), 331–336. http://dx.doi.org/10.1016/j.pbb.2009.04.015.
Nesic, J., Duka, T., Rusted, J.M., Jackson, A., 2011. A role for glutamate in subjective re-
sponse to smoking and its action on inhibitory control. Psychopharmacology (Berl)
Nestor, L., McCabe, E., Jones, J., Clancy, L., Garavan, H., 2011. Differences in ‘bottom-up’
and ‘top-down’ neural activity in current and former cigarette smokers: evidence for neural
substrates which May promote nicotine abstinence through increased cognitive control.
Neuroimage 56 (4), 2258–2275. http://dx.doi.org/10.1016/j.neuroimage.2011.03.054.
Neubert, F.-X., Mars, R.B., Buch, E.R., Olivier, E., Rushworth, M.F., 2010. Cortical and
subcortical interactions during action reprogramming and their related white matter
pathways. Proc. Natl. Acad. Sci. 107 (30), 13240–13245. http://dx.doi.org/10.1073/
pnas.1000674107.
Norman, D.A., Shallice, T., 1985. Consciousness and self-regulation. In: Davidson, R.J.,
Schwarts, G.E., Shapiro, D. (Eds.), Advances in Research and Theory, 4. Plenum Press,
New York, pp. 2–18.
Orr, C., Morioka, R., Behan, B., Datwani, S., Doucet, M., Ivanovic, J., Kelly, C., et al., 2013.
Altered resting-state connectivity in adolescent cannabis users. Am. J. Drug Alcohol
Abuse 39 (6), 372–381. http://dx.doi.org/10.3109/00952990.2013.848213.
Owen, A.M., Evans, A.C., Petrides, M., 1996. Evidence for a two-stage model of spatial work-
ing memory processing within the lateral frontal cortex: a positron emission tomography
study. Cereb. Cortex 6 (1), 31–38. http://dx.doi.org/10.1093/cercor/6.1.31.
Papachristou, H., Nederkoorn, C., Havermans, R., Bongers, P., Beunen, S., Jansen, A., 2013.
Higher levels of trait impulsiveness and a less effective response inhibition are linked to
more intense cue-elicited craving for alcohol in alcohol-dependent patients. Psychophar-
macology (Berl) 228 (4), 641–649. http://dx.doi.org/10.1007/s00213-013-3063-3.
Passetti, F., Clark, L., Mehta, M.A., Joyce, E., King, M., 2008. Neuropsychological predictors
of clinical outcome in opiate addiction. Drug Alcohol Depend. 94 (1–3), 82–91. http://dx.
doi.org/10.1016/j.drugalcdep.2007.10.008.
Patkar, A.A., Murray, H.W., Mannelli, P., Gottheil, E., Weinstein, S.P., Vergare, M.J., 2004.
Pre-treatment measures of impulsivity, aggression and sensation seeking are associated
with treatment outcome for African-American cocaine-dependent patients. J. Addict.
Dis. 23 (2), 109–122.
Paulus, M.P., Tapert, S.F., Schuckit, M.A., 2005. Neural activation patterns of
methamphetamine-dependent subjects during decision making predict relapse. Arch.
Gen. Psychiatry 62 (7), 761–768. http://dx.doi.org/10.1001/archpsyc.62.7.761.
Quednow, B.B., Kühn, K.-U., Hoppe, C., Westheide, J., Maier, W., Daum, I., Wagner, M.,
2006. Elevated impulsivity and impaired decision-making cognition in heavy users of
MDMA (‘ecstasy’). Psychopharmacology (Berl) 189 (4), 517–530. http://dx.doi.org/
10.1007/s00213-005-0256-4.
Reynolds, B., Ortengren, A., Richards, J.B., de Wit, H., 2006. Dimensions of impulsive be-
havior: personality and behavioral measures. Personal. Individ. Differ. 40 (2), 305–315.
http://dx.doi.org/10.1016/j.paid.2005.03.024.
Roberts, G.M.P., Garavan, H., 2010. Evidence of increased activation underlying cognitive
control in ecstasy and cannabis users. Neuroimage 52 (2), 429–435. http://dx.doi.org/
10.1016/j.neuroimage.2010.04.192.
Roberts, G.M.P., Garavan, H., 2013. Neural mechanisms underlying ecstasy-related atten-
tional bias. Psychiatry Res. Neuroimaging 213 (2), 122–132. http://dx.doi.org/10.1016/
j.pscychresns.2013.03.011.
Roberts, C.A., Fairclough, S., Fisk, J.E., Tames, F.T., Montgomery, C., 2013. Electrophysi-
ological indices of response inhibition in human polydrug users. J. Psychopharmacol.
27 (9), 779–789. http://dx.doi.org/10.1177/0269881113492899.
Robinson, T.E., Berridge, K.C., 2003. Addiction. Annu. Rev. Psychol. 54, 25–53. http://dx.
doi.org/10.1146/annurev.psych.54.101601.145237.
Rubio, G., Jiménez, M., Rodrı́guez-Jiménez, R., Martı́nez, I., Iribarren, M.M., Jiménez-
Arriero, M.A., Ponce, G., Avila, C., 2007. Varieties of impulsivity in males with alcohol
dependence: the role of cluster-B personality disorder. Alcohol. Clin. Exp. Res. 31 (11),
Ruiter, D., Michiel, B., Oosterlaan, J., Veltman, D.J., van den Brink, W., Goudriaan, A.E.,
2012. Similar hyporesponsiveness of the dorsomedial prefrontal cortex in problem gam-
blers and heavy smokers during an inhibitory control task. Drug Alcohol Depend.
121 (1–2), 81–89. http://dx.doi.org/10.1016/j.drugalcdep.2011.08.010.
Salmon, E., Van der Linden, M., Collette, F., Delfiore, G., Maquet, P., Degueldre, C.,
Luxen, A., Franck, G., 1996. Regional brain activity during working memory tasks.
Brain 119 (5), 1617–1625. http://dx.doi.org/10.1093/brain/119.5.1617.
Scheurich, A., 2005. Neuropsychological functioning and alcohol dependence. Curr. Opin.
Psychiatry 18 (3), 319–323. http://dx.doi.org/10.1097/01.yco.0000165602.36671.de.
Schmaal, L., Joos, L., Koeleman, M., Veltman, D.J., van den Brink, W., Goudriaan, A.E.,
2013. Effects of modafinil on neural correlates of response inhibition in alcohol-
dependent patients. Biol. Psychiatry 73 (3), 211–218. http://dx.doi.org/10.1016/j.
biopsych.2012.06.032.
Schmidt, R., Leventhal, D.K., Mallet, N., Chen, F., Berke, J.D., 2013. Canceling actions in-
volves a race between basal ganglia pathways. Nat. Neurosci. 16 (8), 1118–1124. http://dx.
doi.org/10.1038/nn.3456.
References 163
Schneider, W., Shiffrin, R.M., 1977. Controlled and automatic human information processing:
I. Detection, search, and attention. Psychol. Rev. 84 (1), 1–66. http://dx.doi.org/10.1037/
0033-295X.84.1.1.
Schweinsburg, A.D., Nagel, B.J., Schweinsburg, B.C., Park, A., Theilmann, R.J., Tapert, S.F.,
2008. Abstinent adolescent marijuana users show altered fMRI response during spatial
working memory. Psychiatry Res. Neuroimaging 163 (1), 40–51. http://dx.doi.org/
10.1016/j.pscychresns.2007.04.018.
Schweinsburg, A.D., Schweinsburg, B.C., Medina, K.L., McQueeny, T., Brown, S.A.,
Tapert, S.F., 2010. The influence of recency of use on fMRI response during spatial work-
ing memory in adolescent marijuana users. J. Psychoactive Drugs 42 (3), 401–412. http://
dx.doi.org/10.1080/02791072.2010.10400703.
Shiffrin, R.M., Schneider, W., 1977. Controlled and automatic human information processing:
II. Perceptual learning, automatic attending and a general theory. Psychol. Rev. 84 (2),
127–190. http://dx.doi.org/10.1037/0033-295X.84.2.127.
Smith, J.L., Mattick, R.P., 2013. Evidence of deficits in behavioural inhibition and perfor-
mance monitoring in young female heavy drinkers. Drug Alcohol Depend. 133 (2),
398–404. http://dx.doi.org/10.1016/j.drugalcdep.2013.06.020.
Smith, J.L., Mattick, R.P., Jamadar, S.D., Iredale, J.M., 2014. Deficits in behavioural inhibi-
tion in substance abuse and addiction: a meta-analysis. Drug Alcohol Depend. 145, 1–33.
Sofuoglu, M., Herman, A.I., Li, Y., Waters, A.J., 2012. Galantamine attenuates some of the
subjective effects of intravenous nicotine and improves performance on a go no-go task in
abstinent cigarette smokers: a preliminary report. Psychopharmacology (Berl) 224 (3),
413–420. http://dx.doi.org/10.1007/s00213-012-2763-4.
Sohn, M.-H., Ursu, S., Anderson, J.R., Andrew Stenger, V., Carter, C.S., 2000. The role of
prefrontal cortex and posterior parietal cortex in task switching. Proc. Natl. Acad. Sci.
97 (24), 13448–13453. http://dx.doi.org/10.1073/pnas.240460497.
Spronk, D.B., Van Wel, J.H., Ramaekers, J.G., Verkes, R.J., 2013. Characterizing the cogni-
tive effects of cocaine: a comprehensive review. Neurosci. Biobehav. Rev. 37 (8),
1838–1859. http://dx.doi.org/10.1016/j.neubiorev.2013.07.003.
Stuss, D.T., Frank Benson, D., 1987. The Frontal Lobes and Control of Cognition and Mem-
ory. In: The IRBN Press, New York, pp. 141–158. http://search.proquest.com/psycinfo/
docview/617353807/941B8AE17B7E49A2PQ/1?accountid¼14679.
Sullivan, E.V., 2003. Compromised pontocerebellar and cerebellothalamocortical systems:
speculations on their contributions to cognitive and motor impairment in nonamnesic
alcoholism. Alcohol. Clin. Exp. Res. 27 (9), 1409–1419. http://dx.doi.org/10.1097/01.
ALC.0000085586.91726.46.
Swann, N.C., Tandon, N., Canolty, R., Ellmore, T.M., McEvoy, L.K., Dreyer, S., DiSano, M.,
Aron, A.R., 2009. Intracranial EEG reveals a time- and frequency-specific role for
the right inferior frontal gyrus and primary motor cortex in stopping initiated responses.
J. Neurosci. 29 (40), 12675–12685. http://dx.doi.org/10.1523/JNEUROSCI.3359-09.2009.
Swann, N.C., Cai, W., Conner, C.R., Pieters, T.A., Claffey, M.P., George, J.S., Aron, A.R.,
Tandon, N., 2012. Roles for the pre-supplementary motor area and the right inferior
frontal gyrus in stopping action: electrophysiological responses and functional and
structural connectivity. Neuroimage 59 (3), 2860–2870. http://dx.doi.org/10.1016/j.
neuroimage.2011.09.049.
Tabibnia, G., Monterosso, J.R., Baicy, K., Aron, A.R., Poldrack, R.A., Chakrapani, S.,
Lee, B., London, E.D., 2011. Different forms of self-control share a neurocognitive
substrate. J. Neurosci. 31 (13), 4805–4810. http://dx.doi.org/10.1523/

JNEUROSCI.2859-10.2011.
Tanabe, J., Tregellas, J.R., Dalwani, M., Thompson, L., Owens, E., Crowley, T., Banich, M.,
2009. Medial orbitofrontal cortex gray matter is reduced in abstinent substance-dependent
individuals. Biol. Psychiatry 65 (2), 160–164. http://dx.doi.org/10.1016/j.
biopsych.2008.07.030.
Tapert, S.F., Schweinsburg, A.D., Drummond, S.P., Paulus, M.P., Brown, S.A., Yang, T.T.,
Frank, L.R., 2007. Functional MRI of inhibitory processing in abstinent adolescent mar-
ijuana users. Psychopharmacology (Berl) 194 (2), 173–183. http://dx.doi.org/10.1007/
s00213-007-0823-y.
Torregrossa, M.M., Quinn, J.J., Taylor, J.R., 2008. Impulsivity, compulsivity, and habit: the
role of orbitofrontal cortex revisited. Biol. Psychiatry 63 (3), 253–255. http://dx.doi.org/
10.1016/j.biopsych.2007.11.014.
Townshend, J.M., Duka, T., 2005. Binge drinking, cognitive performance and mood in a pop-
ulation of young social drinkers. Alcohol. Clin. Exp. Res. 29 (3), 317–325. http://dx.doi.
org/10.1097/01.ALC.0000156453.05028.F5.
Volkow, N.D., Fowler, J.S., Wang, G.-J., Telang, F., Logan, J., Jayne, M., Ma, Y., Pradhan, K.,
Wong, C., Swanson, J.M., 2010. Cognitive control of drug craving inhibits brain reward
regions in cocaine abusers. Neuroimage 49 (3), 2536–2543. http://dx.doi.org/10.1016/j.
neuroimage.2009.10.088.
von Geusau, N.A., Stalenhoef, P., Huizinga, M., Snel, J., Richard Ridderinkhof, K., 2004. Im-
paired executive function in male MDMA (‘ecstasy’) users. Psychopharmacology (Berl)
Vonmoos, M., Hulka, L.M., Preller, K.H., Jenni, D., Schulz, C., Baumgartner, M.R.,
Quednow, B.B., 2013. Differences in self-reported and behavioral measures of impulsivity
in recreational and dependent cocaine users. Drug Alcohol Depend. 133 (1), 61–70. http://
dx.doi.org/10.1016/j.drugalcdep.2013.05.032.
Waters, A.J., Shiffman, S., Sayette, M.A., Paty, J.A., Gwaltney, C.J., Balabanis, M.H., 2003.
Attentional bias predicts outcome in smoking cessation. Health Psychol. 22 (4), 378–387.
http://dx.doi.org/10.1037/0278-6133.22.4.378.
Weafer, J., de Wit, H., 2013. Inattention, impulsive action, and subjective response to D-am-
phetamine. Drug Alcohol Depend. 133 (1), 127–133. http://dx.doi.org/10.1016/j.
Whelan, R., Conrod, P., Poline, J.B., Banaschewski, T., Barker, G.J., Bellgrove, M.A.,
Büchel, C., Byrne, M., Cummins, T., Fauth-Bühler, M., Flor, H., Gallinat, J.,
Heinz, A., Ittermann, B., Lourdusamy, A., Mann, K., Martinot, J.-L., Lalor, E.C.,
Lathrop, M., Loth, E., Paus, T., Rietschel, M., Smolka, M.N., Spanagel, R.,
Stephens, D., Struve, M., Thyreau, B., Vollstaedt-Klein, S., Robbins, T.W.,
Schumann, G., Garavan, H., the IMAGEN consortium, 2012. Adolescent impulsivity phe-
notypes characterized by distinct brain networks. Nat. Neurosci. 15, 920–925.
CHAPTER
Neuroscience of inhibition
for addiction medicine: from
prediction of initiation to
prediction of relapse
9
Scott J. Moeller*,†,1, Lucia Bederson{, Nelly Alia-Klein*,†, Rita Z. Goldstein*,†,1
*Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
†
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
{
Department of Psychology, New York University, New York, NY, USA
1
Corresponding authors: Tel.: +1-212-824-8973; Fax: +1-212-803-6743. Tel.: +1-212-824-9312;
Fax: +1-212-996-8931, e-mail address: [email protected]; [email protected]
Abstract
A core deficit in drug addiction is the inability to inhibit maladaptive drug-seeking behavior.
Consistent with this deficit, drug-addicted individuals show reliable cross-sectional differ-
ences from healthy nonaddicted controls during tasks of response inhibition accompanied
by brain activation abnormalities as revealed by functional neuroimaging. However, it is less
clear whether inhibition-related deficits predate the transition to problematic use, and, in turn,
whether these deficits predict the transition out of problematic substance use. Here, we review
longitudinal studies of response inhibition in children/adolescents with little substance expe-
rience and longitudinal studies of already addicted individuals attempting to sustain absti-
nence. Results show that response inhibition and its underlying neural correlates predict
both substance use outcomes (onset and abstinence). Neurally, key roles were observed for
multiple regions of the frontal cortex (e.g., inferior frontal gyrus, dorsal anterior cingulate cor-
tex, and dorsolateral prefrontal cortex). In general, less activation of these regions during re-
sponse inhibition predicted not only the onset of substance use, but interestingly also better
abstinence-related outcomes among individuals already addicted. The role of subcortical
areas, although potentially important, is less clear because of inconsistent results and because
these regions are less classically reported in studies of healthy response inhibition. Overall, this
review indicates that response inhibition is not simply a manifestation of current drug addic-
tion, but rather a core neurocognitive dimension that predicts key substance use outcomes.
Early intervention in inhibitory deficits could have high clinical and public health relevance.

165
166 CHAPTER 9 Longitudinal studies of response inhibition in addiction
Keywords
Response inhibition, Inhibitory control, Drug addiction, Developmental trajectories, Clinical
outcome, fMRI, Longitudinal designs
1 INTRODUCTION
Drug addiction is a chronically relapsing disorder marked by dysregulated inhibitory
control, which may contribute to or exacerbate the addicted individual’s ability to
restrain drug-taking (Goldstein and Volkow, 2011; Kalivas and Volkow, 2005). Neu-
roimaging studies utilizing functional magnetic resonance imaging (fMRI) have con-
sistently identified abnormalities in brain function during response inhibition in
currently addicted individuals across multiple drugs of abuse (Luijten et al., 2014;
Smith et al., 2014). Nevertheless, an enduring problem of such cross-sectional stud-
ies is the inability to infer the direction of association. Longitudinal studies offer an
exciting opportunity to test whether core drug-relevant neurocognitive deficits (e.g.,
in response inhibition) predate the transition into and out of problematic drug use. In
this way, one can evaluate whether such deficits in drug addiction represent an epi-
phenomenon or an actual predisposing factor.
Accordingly, the goal of the current review is to examine the extent to which per-
formance- and/or neural-related decrements during tasks of inhibitory control pre-
cede the transition to drug use/addiction, and then whether such decrements
predict clinical outcomes when already addicted individuals seek treatment or
attempt to abstain. In particular, we seek to evaluate the hypothesis that impaired
response inhibition is not simply a concurrent symptom of drug addiction, but instead
a core neurocognitive dimension that predicts key substance use outcomes. We con-
centrate on longitudinal studies, largely those reported within the last 10 years, which
have examined prospective associations between inhibitory control and the depen-
dent variable of interest (drug use initiation or escalation, dependence, relapse, or
abstinence). Most of the fMRI studies reviewed here report the results of task-
induced activations (e.g., activity that occurs during a condition of response inhibi-
tion contrasted with activity during a condition of prepotent response). Other studies
used task-related functional connectivity (i.e., the covariation between the fMRI time
courses of a given voxel and other voxels in the brain), which offers a promising
complement to task-based activation studies. The main literature review itself is or-
ganized into two parts. Part 1 discusses adolescent longitudinal studies that use tasks
of inhibitory control to predict future drug use or transition into drug dependence.
Part 2 discusses adult longitudinal studies that use tasks of inhibitory control to pre-
dict clinical and treatment outcomes in already addicted individuals. We conclude
with a summary of findings and a discussion of future research directions.
We exclude from this review studies that involved passive exposure to
drug-related stimuli, studies that used tasks associated with the receipt of reward,
or studies that reported addiction-related abnormalities in brain structural integrity.
Reviews that address these important topics can be found elsewhere (e.g., Garavan
2 Commonly used response inhibition tasks in drug addiction 167
et al., 2013; Heitzeg et al., 2015; Jasinska et al., 2014; note some overlap in currently
included studies with those from Heitzeg et al. (2015). This review also excludes
behavioral addictions (e.g., gambling, food, sex, or video games) and studies that
use event-related potentials, as more longitudinal studies in these fields are needed
before firm conclusions about prospective relationships can be drawn. Studies that
focus on family history (or other risk factors) as the main grouping variable are also
excluded (e.g., Hardee et al., 2014). Finally, for brevity and focus, we also exclude
tasks of inhibition that measure related constructs (e.g., error awareness; Hester et al.,
2009), or studies that incorporate pharmacological (Moeller et al., 2014; Schmaal
et al., 2013) or genetic (Filbey et al., 2012) modulation.
2 COMMONLY USED RESPONSE INHIBITION TASKS

IN DRUG ADDICTION
Three of the most commonly used inhibitory control tasks, in order from simplest to
most cognitively complex, include go/no-go tasks (Chambers et al., 2009), stop-
signal tasks (Aron et al., 2014; Verbruggen and Logan, 2008), and Stroop tasks
(MacLeod, 1991; Smith and Ersche, 2014). These tasks collectively measure a per-
son’s ability to modify or stop a behavior, particularly when the behavior may not be
optimal or advantageous, or is perceived as incorrect. In go/no-go tasks, participants
respond as quickly as possible to frequent go stimuli and inhibit responses to infre-
quent no-go stimuli. Correct nonresponses on no-go trials reflect the ability to exert
inhibitory control over behavior. In stop-signal tasks, the goal is to successfully in-
hibit (stop) an action that has already begun. Participants respond to an ongoing se-
quence of stimuli; on some (stop) trials, however, a signal is presented (e.g., a tone, a
change in stimulus display) after the stimulus onset that instructs participants to halt
their response on that trial. The paradigm is typically configured to find the inflection
point in which 50% of stop trials are unsuccessful relative to the mean reaction time;
the longer this stop-signal reaction time (SSRT), the worse the inhibitory control. In
Stroop tasks, participants must override a more automatic response tendency (read-
ing a word) and instead respond with a task-specific demand (responding to the ink
color of the word). Stroop tasks can be purely cognitive: in the classical color-word
Stroop, participants respond to the ink color of color words (e.g., “blue”) presented in
either the congruent font (blue font) or an interfering incongruent font (e.g., red font).
Stroop tasks can also be emotional: interference can be introduced by attentional bias
or current concerns of the individual. In the case of drug addiction, individuals can be
instructed to ignore the semantic content of drug-related words (e.g., “pipe”) and in-
stead respond to their font color; typically, the reaction time to drug words is longer
than for neutral words (e.g., “vase”), indicating impaired response inhibition (Cox
et al., 2006). An important caveat is that these tasks, while tapping into inhibitory
control, also depend on other executive, attentional, or emotional processing func-
tions. For example, some have argued that Stroop tasks tap into different higher-
order executive functions than go/no-go and stop-signal tasks, such as compulsivity
and impulsivity, respectively (Fineberg et al., 2014).
All three of these tasks have reliably yielded activations in regions of interest
(ROIs)/networks known to be engaged during inhibitory control. These include
the inferior frontal gyrus (IFG), anterior cingulate cortex (ACC) (especially its
dorsal/motor subregion), middle frontal and superior frontal gyri (MFG/SFG)
[which includes the dorsolateral prefrontal cortex (DLPFC)], parietal lobe, and
pre-supplementary motor area (pre-SMA) (Bari and Robbins, 2013; Cieslik et al.,
2015; Fig. 1). Importantly, some of these same regions are consistently identified
as being disrupted in currently addicted individuals performing the tasks (for
recent, comprehensive reviews on this topic, see Luijten et al., 2014; Smith et al.,
2014). These studies and reviews in current drug dependence suggest pertinent
regions/networks to spotlight for longitudinal prediction (Fig. 1), which is the focus
of the remainder of this review.
FIGURE 1
Schematic of the current review. Response inhibition is associated with performance and
neural correlates of response inhibition (regions/networks include IFG, dACC/pre-SMA,
DLPFC, and parietal lobe), which together prospectively predict substance use initiation and
clinical/treatment outcomes. Blue arrows (gray in the print version) reflect concurrent
associations; red arrows (dark gray in the print version) reflect longitudinal predictions; skinny
black arrows are descriptive. Rectangles reflect measured variables; circles reflect latent
variables (i.e., variables defined by other measured variables, whether explicitly included in
the schematic or not). The broken text and arrows of the addiction circle signify implied
relationships (i.e., not the focus of the current review). IFG ¼ inferior frontal gyrus,
dACC ¼ dorsal anterior cingulate cortex, pre-SMA ¼ pre-supplementary motor area,
DLPFC ¼ dorsolateral prefrontal cortex.
Brain activation maps are adapted from a previous meta-analysis of response inhibition in health
(Cieslik et al., 2015) (with permission from Elsevier).
3 Part 1: progression into addiction/problematic substance use 169
3 PART 1: PROGRESSION INTO ADDICTION/PROBLEMATIC

SUBSTANCE USE (TABLE 1)
3.1 GO/NO-GO STUDIES
A moderately large sample of adolescents performed a go/no-go task during fMRI at
baseline and then again 18 months later. More left angular/supramarginal gyrus ac-
tivation and less ventromedial prefrontal cortex (vmPFC) activation to the no-go ver-
sus go trials at baseline predicted an increase in drug use occasions at follow-up (i.e.,
accounting for baseline drug use)—particularly in those who were already heavier
users (Mahmood et al., 2013). Another longitudinal fMRI study tested for changes
over the first year of college during an emotionally salient go/no-go task that
instructed participants to respond to alcohol cues compared with nonalcohol cues;
here, the dependent variable was task-related functional connectivity. Young adults
were scanned three times (summer, first semester, second semester). At the second
assessment (during which respondents reported an increase relative to the first as-
sessment in the negative consequences of alcohol use, such as losing consciousness
during drinking or performing poorly on an exam because of drinking), functional
connectivity was increased among a network of regions implicated in response in-
hibition and cognitive control (e.g., bilateral DLPFC, rostral ACC, dorsal ACC)
(Beltz et al., 2013).
Even more illuminating, however, are studies that begin tracking youth before
they have begun experimenting with addictive substances. In one study, an fMRI
go/no-go task was used at two study sessions to compare adolescents who were ini-
tially nondrinkers but later transitioned into heavy drinking against adolescents who
remained nondrinkers during both assessments. Adolescents who later transitioned
into heavy drinking showed less fMRI response to no-go versus go trials in the MFG,
parietal cortex, putamen, and cerebellum. Interestingly, these effects were reversed
at the second scanning session such that the adolescent heavy drinkers showed in-
creased fMRI activation in these regions (except in the putamen, where no group
differences were observed in the second session) (Wetherill et al., 2013). Results
were interpreted to indicate that the reduced fMRI activation before drinking could
reflect vulnerability, whereas the increased fMRI activation after drinking could re-
flect compensation. Another fMRI study investigated adolescents again with initially
very limited substance use experience, classifying them at follow-up into those who
transitioned to heavy use of alcohol versus those who remained nonusers. Similar
results were reported, whereby youth who later transitioned into heavy alcohol
use had less activation in multiple brain regions encompassing the IFG, DLPFC, pu-
tamen, middle temporal gyri, and inferior parietal lobules (Norman et al., 2011).
More recently, preteens (9–12 years) performed an fMRI go/no-go task at baseline;
4 years later, participants completed assessments of substance use, which were used
to create matched groups of substance users and nonsubstance users. In contrast to
the other studies, there were no significant fMRI differences between the groups dur-
ing successful no-go inhibition at baseline. Instead, nonusers showed increased
Table 1 Prediction of Drug Use Initiation
Participants Mean Time Main
(Retention Age Sex: Between Results,
Study Rate) (SD) M/F Race Disorder Status RI Task Assessments Behavioral Main Results, Imaging
Go/no-go tasks
Beltz et al. (2013) N ¼ 11 (91.01%) 18–19 5/6 NR NR Go/no-go T1–T2: 2 NS Task functional interconnectivity: " B DLPFC,
fMRI months ACC over time
T2–T3: 3
months
Heitzeg et al. N ¼ 45 100% C Externalizing: Go/no-go T1–T2: 4 RT: PU # Contrast: failed RI > correct RI; NU " PU: L MFG;
(2014) HC, n ¼ 19 10.9 15/4 CBCL & YSR fMRI years NU L MFG neg corr externalizing
(1.1)
NU, n ¼ 13 10.9 10/3
(0.9)
PU, n ¼ 13 11.0 10/3
(1.0)
Norman et al. N ¼ 38 80% C Substance use: Go/no-go T1–T2: 4.2 NS Contrast: HU no-go < HC no-go: " L DLPFC,
(2011) HU: n ¼ 21 13.9 11/10 CDDR & DSM-IV fMRI years L superior MFG, R IFG, B medial FG,
(0.9) Externalizing: B paracentral lobules, pre-SMA, L ACC, L Put,
CBCL L MTG, R MTG, B IPL; " R IFG, L ACC, R MTG,
HC: n ¼ 17 13.4 8/9
L IPL neg corr T2 CBCL attention problems
(0.7)
Mahmood et al. N ¼ 80 CDDR Go/no-go T1–T2: NS Contrast: no-go > go: HF users: # vmPFC pos
(2013) HF, n ¼ 39 17.4 28/11 76% C fMRI 18 months corr T2 Drug & Alc Sx
(0.9)
LF, n ¼ 41 17.6 30/11 79% C
(1.0)
Wetherill et al. N ¼ 40 55% C, Substance use: Go/no-go T1–T2: 3 + NS group Contrast: HU no-go < HC no-go: T1: " B MFG,
(2013) HU, n ¼ 20 14.7 11/9 20% H, CDDR and fMRI years difference; IPL, L Put, L cerebellum; T2: # B MFG, R inferior
(1.1) 15% DSM-IV RI " with parietal lobule, L cerebellum; HU: " R MFG pos
multi, 5% Psychopathology/ age corr T2 drinking
HC, n ¼ 20 14.1 11/9
As, 5% A externalizing:
(1.2)
CBCL, YSR, &
ASR
Stop-signal tasks
Fernie et al. (2013) N ¼ 287 (94.4%) 12–13 NR NR NR Stop-signal T1–T2: 6 " SSRT pos NA
behavior months corr T2
T2–T3: 6 Drinking
months
T3–T4: 6
months
T4–T5: 6
months
Nigg et al. (2006) N ¼ 498 12–14 362/ 100% C Alc/drug use: Stop-signal T1–T2: 3 " SSRT pos NA
136 DDHQ behavior years corr T2
drinking &
drug
problems
Wong et al. (2010) N ¼ 386 15–17 292/94 100% C DDHQ-Y & DISC Stop-signal T1–T2: " SSRT pos NA
behavior 3 years corr T2 Alc
T2–T3: Sx
3 years
T3–T4:
3 years
T4–T5: 3
years
Whelan et al. N ¼ 2650 NR ESPAD Stop-signal T1–T2: 2 NR Contrast: failed RI: " R precentral
(2014) BD, n ¼ 115 14.62 4/66 fMRI years gyrus pos corr with T2 binge drinking
(0.39)
FBD, n ¼ 121 14.45 69/52
(0.40)
HC, n ¼ 150 14.53 70/80
(0.43)
Stroop tasks
Peeters et al. N ¼ 347 (72.0%) 13.6 330/44 75% Alc quantity: cwStroop T1–T2: 6 Poor RI: Alc NA
(2013) (0.9) Dutch 14-item scale behavior; months approach
25 non- Severity: CRAFFT approach- pos corr T2
Dutch avoidance Alc use
behavior
Notes: As, Asian; A, African American; Alc, alcohol; ASR, Adult Self-Report; B, bilateral; C, Caucasian; CBCL, Child Behavioral Checklist; CDDR, Customary Drinking and Drug Use Record; cwStroop, Stroop with classical color-word stimuli;
DDHQ, Drinking and Other Drug Use History Questionnaire; DDHQ-Y, Drinking and Other Drug Use History Questionnaire—Youth Version; DISC, Diagnostic Interview Schedule for Children; DLPFC, dorsolateral prefrontal cortex; ESPAD,
European School Survey Project on Alcohol and Drugs; FBD, future binge drinker; FH+, family history AUD positive; Fas, false alarms; FH, family history AUD negative; H, Hispanic; HC, healthy control; HF, high frequency; HU, heavy user; IFG,
inferior frontal gyrus; IPL, inferior parietal lobe; L, left; LF, low frequency; MFG, middle frontal gyrus; MTG, middle temporal gyrus; neg corr, negative correlation; NA, not applicable; NR, not reported; NS, not significant; NU, nonuser; PFC,
prefrontal cortex; pos corr, positive correlation; PU, problem-user; Put, putamen; pre-SMA, pre-supplementary motor area; SSRT, stop-signal reaction time; R, right; RI, response inhibition; Sx, symptoms; T, time; TRF, Teacher’s Report Form;
YAAPST, Young Adult Problems Screening Test; vmPFC, ventromedial prefrontal cortex; YSR, Youth Self-Report.
activation relative to users during unsuccessful inhibition versus successful inhibi-

tion in the left MFG (DLPFC); DLPFC activation predicted outcome (group mem-
bership) over and above the effects of externalizing behavior (Heitzeg et al., 2014).
This different pattern of effects could be due to the different fMRI contrast (error-
related processing).
3.2 STOP-SIGNAL STUDIES

Four hundred ninety-eight children from 275 families from a high-risk, prospectively
followed cohort completed executive function measures in early and late adoles-
cence, with the goal of predicting lifetime drinking and drug-related ratings in late
adolescence; multilevel models controlling for various potential confounds showed
that poorer response inhibition (i.e., higher SSRT) predicted the onset of future drug
and alcohol use (Nigg et al., 2006). Moreover, in the same high-risk sample, poorer
response inhibition in late adolescence predicted alcohol-related problems in young
adulthood (e.g., driving while intoxicated or experiencing an alcohol-induced black-
out) (Wong et al., 2010).
A different research group similarly used a multiwave longitudinal study (five
assessments over 2 years) to test associations between the behavioral stop-signal task
and alcohol use in adolescents (Fernie et al., 2013). Data were analyzed using sophis-
ticated cross-lagged analyses, which enable investigation of the relationships be-
tween response inhibition at time 1 and alcohol use at time 2 while controlling
for cross-sectional associations between these variables at both time points and
for their stability over time. Results showed that stop-signal performance prospec-
tively predicted alcohol involvement, whereas the reverse association (alcohol in-
volvement predicting response inhibition) did not reach significance. These
analyses, which approximate causal relationships between variables in a nonexperi-
mental design, suggest that response inhibition in adolescence confers vulnerability
toward future substance use.
In an elegant, recent fMRI study, machine learning techniques were used to in-
tegrate multimodal self-report, structural and functional imaging, and genetics data
in service of predicting concurrent and future binge drinking in a large sample of
adolescents. In the longitudinal arm, fMRI activation in the precentral gyrus to re-
sponse inhibition failures predicted future binge drinking (Whelan et al., 2014).
3.3 STROOP STUDIES

Few studies have used Stroop tasks to predict emerging substance use problems. One
behavior-only study used a Stroop task to stratify adolescents into those with stronger
or weaker response inhibition (weaker response inhibition was defined as higher
incongruent > neutral response reaction time). The task itself was an approach-
avoidance paradigm that used stimuli depicting alcohol or soda, and participants
were instructed to either pull (approach) or push (avoid) a lever in response to the
stimuli. Results showed that greater alcohol approach tendencies (i.e., faster reaction
4 Part 2: prediction of clinical outcome 173
time to pull the lever toward than push the lever away) predicted alcohol use at
6-month follow-up only in the adolescents with weaker Stroop-assessed inhibition
(Peeters et al., 2013).
3.4 PART 1 SUMMARY

These studies suggest that performance on tasks of response inhibition in adoles-
cence/young adulthood predicts future initiation into substance use. Despite some
exceptions (and although additional studies utilizing the Stroop task are needed),
the general pattern of results suggests underactivations during the response inhibition
trials in key inhibition-related regions in the individuals who would later become
substance users; an opposite (hyperactivation) pattern seemed to occur when exam-
ining response failure. The most consistent neural correlate of response inhibition
was the DLPFC, which is a core region in response inhibition but also in the imple-
mentation of cognitive control more generally (Egner et al., 2008; Kerns et al., 2004).
Other regions identified in multiple studies included the parietal cortex and the pu-
tamen. The precentral gyrus also deserves mention, given this region’s emergence in
a well-powered and well-controlled study (Whelan et al., 2014). These neural under-
activations during response inhibition in the individuals who would later develop
problematic drug use were typically observed in the absence of behavioral differ-
ences between the groups (Table 1). Lack of group differences on task performance
suggests that these fMRI differences are potentially marking abnormal neural activ-
ity (rather than, for example, an inability to perform the task). Taken together, inhi-
bition problems and associated aberrant brain response during the exertion of
inhibitory control appear to predate substance use.
4 PART 2: PREDICTION OF CLINICAL OUTCOME IN ALREADY

ADDICTED INDIVIDUALS (TABLE 2)
4.1 GO/NO-GO STUDIES
In an interesting study of smokers motivated to quit, fMRI during a go/no-go task
(successful no-go versus go events) was used to predict outcome via an experience
sampling method (a unique contribution to this literature); as part of these assess-
ments, participants responded eight times per day for 3 weeks about their craving
and cigarettes smoked (Berkman et al., 2011). The IFG, pre-SMA, and basal ganglia
were selected as ROIs. Results revealed a positive correlation between craving at one
time point and smoking at the next time point. Interestingly, this relationship was
moderated by all three ROIs such that individuals who had higher fMRI activations
in these regions to the no-go stimuli had a blunted correlation between craving and
smoking. This finding could suggest that enhanced neural response during response
inhibition reflects a greater capacity to exert top-down control over impulses
(e.g., craving) [although it should be noted that other studies have interpreted
Table 2 Prediction of Clinical Outcome
Participants Mean Time
(Retention Age Sex: Abst Disorder Treatment Between Main Results, Main Results,
Study Rate) (SD) M/F Race Length Status Status RI Task Assessments Behavioral Imaging
Go/no-go tasks
Berkman N ¼ 31 46 (9.7) 16/15 52% NR >10 cig/ Cessation Go/no-go T1–T2: 4 NS Contrast:
et al. (2011) C, day program fMRI weeks no-go > go: " IFG,
26% H BG, & pre-SMA
19% A pos corr with
3% O attenuation of
craving-smoking link
Prisciandaro CD: 41.2 5/1 83% A 72 h DSM-IV Outpatient Drug no/ T1–T2: 1 week NS Contrast:
et al. (2013) N ¼ 30 (ReL: (8.3) for CD no-go fMRI no-go > go: "
n ¼ 6; no-ReL: B postcentral gyri pos
corr with urine+
n ¼ 24) 48.4 20/4 83% A
(8.7)
Stop-signal tasks
Jakubczyk AD: N ¼ 254 44.2 189/65 NR DSM-IV Inpatient Stop-signal T1–T2: NS NA
et al. (2013) (10.2) for AD behavior 12 months
Luo et al. CD: N ¼ 97 29% C 2–4 DSM-IV Inpatient Stop-signal T1–T2: NS Contrast: stop
(2013) ReL: n ¼ 80 39.1 27/53 67% weeks for CD fMRI 14 days error > stop correct:
(7.5) A T1–T3: in female CD, #
thalamus & dACC
pos
No-ReL: 43.0 7/10 4% O 30 days corr relapse; in male
n ¼ 17 (7.3) T1–T4: CD, # L insula &
60 days dACC pos corr
T1–T5: relapse
90 days
Stroop tasks
Brewer et al. CD: N ¼ 20 38.6 12/8 30% C 28 days DSM-IV Outpatient cwStroop NR RT: " Contrast:
(2008) (9.3) 50% A for CD fMRI incong > cong incong < cong; "
20% H pos corr Tx R Put pos corr
retention urine & longest
abst; R putamen,
L vmPFC & left
PCC pos corr longest
abst; # DLPFC pos
corr Tx retention
Carpenter CD: N ¼ 25 37 (7.1) 22/3 36% C 14 days DSM-IV Outpatient dStroop 24 weeks RT: " NA
et al. (2012) 28% A for CD behavior drug > neutral
24% H pos corr Phase
3% O II Tx and urine
Carpenter N ¼ 80 NR DSM-IV Outpatient (Substance- NR RT: In CD, " NA
et al. (2006) CD: n ¼ 45 38.6 33/12 31% for CD/MJ matched) cocaine >
(8.1) C dStroop neutral pos corr
behavior urine + and
MJ: n ¼ 25 32.4 20/5 24%
shorter Tx; in
(8.9) A
MJ and HD, NS
HD: n ¼ 10 32.4 9/1 33%
(6.6) H
Cox et al. N ¼ 30 NR NR DSM-IV Inpatient dStroop AD: 24 days RT: in AD ReL NA
(2002) AD: 41.9 11/3 for AD behavior HC: 28 days but not non-
n ¼ 14 (ReL: (10.6) ReL, "
n ¼ 9; alcohol >
No-ReL: neutral
n ¼ 5)
HC: n ¼ 16 37.3 4/12
(10.3)
Devito et al. SUD: n ¼ 12 37.2 7/5 NR NR DSM-IV RCT cwStroop T1–T2: RT: SUD < HC, Contrast:
(2012) (9.5) for SUD fMRI 8 weeks but # incong RT incong > cong
HC: n ¼ 12 31.0 5/7 in SUD at T2 T2 < T1
(8.6) SUD < HC: # STN/
VTA, GP, thal &
hypothal
Marhe et al. CD: N ¼ 26 38.7 22/4 NR NR DSM-IV Inpatient dStroop T1–T2: 3 RT: cocaine Contrast:
(2013) (9.2) for CD fMRI months > neutral cocaine > neutral:
" R dACC ROI pos
corr cocaine use
days
Mitchell et al. CD: N ¼ 15 39.0 6/9 CD: NR DSM-IV Outpatient cwStroop T1–T2: 8–12 NS Measure: intrinsic
(2013) (10.4) 40% for CD fMRI weeks connectivity:
HC: 40.0 7/8 C, CD < HC: R caudate,
N ¼ 15 (7.4) 66.7% B OFC, IFG, insula,
A thal, SN and VS; "
HC: connectivity in
53% B thalamus, VS, & SN
C, neg corr abst during
47% A Tx & pos corr urine+
Moeller et al. CD: 41.4 11/4 53% A 3 DSM-IV Mix dStroop T1–T2: 6.4 RT: T2 < T1 Contrast: T2 > T1;
(2012b) N ¼ 15 (Tx- (9.1) 33% C weeks for CD inpatient/ fMRI (1) months neutral " B midbrain (VTA/
seeking) 13% O outpatient SN) & R thal, neg corr
CD: N ¼ 13 42.5 12/1 77% A simulated drug-
(active users) (5.9) 8% C seeking
15% O
Continued
Table 2 Prediction of Clinical Outcome—cont’d
Participants Mean Time
(Retention Age Sex: Abst Disorder Treatment Between Main Results, Main Results,
Study Rate) (SD) M/F Race Length Status Status RI Task Assessments Behavioral Imaging
HC: N ¼ 13 39.6 11/2 69% A

(4.9) 23% C
8% O
Verdejo- CD: N ¼ 131 33.9 120/11 NR 15 days DSM-IV Therapeutic cwStroop T1–T2: 15–30 RT NA
Garcia et al. (21.6) for CD community behavior days incong > cong:
(2012) cocaine
+ heroin
comorbid <
cocaine only;
RT trend pos
corr Tx
retention
Worhunsky CD: N ¼ 20 38.6 12/8 CD: NR DSM-IV Outpatient cwStroop 8 weeks RT: NS Measure: ICA: "
et al. (2013) (9.3) 30% for CD fMRI treatment Errors: subcortical- & ventral
HC: N ¼ 20 36.8 12/8 C, CD > HC frontostriatal
(8.9) 50% A, networks pos corr
20% O urine; #
HC: frontocingular
70% network pos corr
C, Tx wks
30% A
Notes: As, Asian; A, African American; Abst, abstinence; ACC, anterior cingulate cortex; AD, alcohol use disorder; ASR, Adult Self-Report; B, bilateral; BG, basal ganglia; C, Caucasian; CBCL, Child Behavior Checklist; CD,
cocaine dependence; Cong, congruent; CDDR, Customary Drinking and Drug Use Record; cwStroop, Stroop with classical color-word stimuli; DDHQ-Y, Drinking and Other Drug Use History Questionnaire-Youth Version;
DISC, Diagnostic Interview Schedule for Children; DLPFC, dorsolateral prefrontal cortex; dStroop, Stroop with drug-associated stimuli; GP, globus pallidus; H, hispanic; HC, healthy control; HD, heroin dependence; ICA,
independent components analysis; IFG, inferior frontal gyrus; Incong, incongruent; ITC, inferior temporal cortex; IRAP, Implicit Relational Assessment Procedure; L, left; Lent Nucl, lentiform nucleus; MFG, middle frontal
gyrus; MJ, Marijuana Dependence; MTG, middle temporal gyrus; neg corr, negative correlation; NA, not applicable; NR, not reported; No-ReL, nonrelapsers; NS, not significant; O, other race; PFC, prefrontal cortex; pre-
SMA, pre-supplementary motor area; Put, putamen; R, right; ReL, relapsers; RCT, randomized clinical trial; RI, response inhibition; ROI, region of interest; R-SAT, Regulation—Revised Strategy Application Test; SFG,
superior frontal gyrus; STG, superior temporal gyrus; SN, substantia nigra; STN, subthalamic nucleus; SUD, substance use disorder; T, time; Thal, thalamus; Tx, treatment; urine+, positive urine result; urine, negative urine
result; vmPFC, ventromedial prefrontal cortex; VS, ventral striatum; VTA, ventral tegmental area; YSR, Youth Self-Report.
such enhanced activation as reflecting compensation (Wetherill et al., 2013)]. In a

secondary analysis of this study, the basal ganglia ROI (but not the other two ROIs)
predicted reduced smoking across 4 weeks (objectively measured by breath CO)
(Berkman et al., 2011).
In another fMRI study (this one using a more standard analysis methodology),
increased activation in a different region (the postcentral gyrus, to all no-go events
versus all go events) predicted treatment outcome 1 week later (positive cocaine
urine screen) (Prisciandaro et al., 2013). Important caveats of this study are that these
participants were also included in a treatment trial that administered D-cycloserine,
and they also completed a cue-reactivity task during the same scanning session.
4.2 STOP-SIGNAL STUDIES

In an fMRI study, a moderately sized cohort of treatment-seeking cocaine-dependent
individuals completed the stop-signal task and was followed over 3 months to predict
clinical outcome. Decreased activation in the dorsal ACC during error-related pro-
cessing (stop error versus stop success) predicted relapse in males and females (note
that males and females also exhibited some differential activations that predicted re-
lapse: decreased thalamus activation in females; decreased insula activation in
males) (Luo et al., 2013). In contrast, in a behavior-only study of treatment-seeking
alcohol-dependent individuals, the stop-signal task administered at baseline did not
predict 12-month outcome; instead, 12-month outcome was predicted by genetic var-
iation (type 2A serotonin receptor polymorphism) ( Jakubczyk et al., 2013). Notable
differences between these studies include the use of fMRI and the length of the
follow-up period (3 versus 12 months).
4.3 STROOP STUDIES

In a behavior-only study examining the variables that predict treatment retention in a
therapeutic community, participants completed a battery of neuropsychological
measures including the color-word Stroop task. Better Stroop task performance (both
the standard inhibition measure and a second measure assessing switching) signifi-
cantly predicted better 3-month outcome, but these results did not survive the au-
thors’ correction for multiple comparisons (Verdejo-Garcia et al., 2012). Other
behavioral studies used emotional (drug) Stroop tasks. In an early study of alcohol
abusers, participants completed an alcohol Stroop task at baseline and then again 4
weeks later. Compared with control participants and alcohol abusers who completed
treatment, alcohol abusers who did not complete treatment had alcohol-related inter-
ference scores that increased from baseline to follow-up (Cox et al., 2002). A caveat
of this study is the small sample sizes in each group (n ¼ 5 participants who remained
abstinent or had a small lapse; n ¼ 9 participants who relapsed or failed to maintain
contact with a counselor). In another earlier study, treatment-seeking drug-addicted
individuals performed a drug Stroop task, with the stimuli content matched to the
participants’ particular substance problem (e.g., cocaine stimuli for individuals
addicted to cocaine) (Carpenter et al., 2006). Results showed that cocaine Stroop
interference scores predicted more cocaine positive urines and shorter treatment du-
ration in the cocaine participants, but similar substance-specific analyses were not
significant in individuals in treatment for marijuana or heroin (but note smaller sam-
ple sizes in these latter two groups compared with the cocaine group). In contrast,
another study from the same lead author showed that drug Stroop interference scores
were positively correlated with a greater likelihood of continuing with treatment (en-
tering a Phase II, which included providing negative cocaine urine screens)
(Carpenter et al., 2012). This latter result could indicate that the interference scores
in this case were tapping into a hypervigilance toward the cocaine cues to sustain
commitment to the treatment process (Moeller and Goldstein, 2014). These conflict-
ing findings remain to be reconciled, but could include variability in the character-
istics of the participants (e.g., abstinence lengths) and/or the therapeutic context
(e.g., presence of a voucher system) (Carpenter et al., 2012).
A growing number of fMRI studies have used Stroop tasks to predict clinical out-
come in already addicted individuals. In one of the first studies of its kind,
20 treatment-seeking cocaine-dependent individuals performed an fMRI color-word
Stroop task prior to initiating treatment. Interestingly, higher behavioral Stroop in-
terference predicted better clinical outcomes (more weeks in treatment). Analysis of
the fMRI data showed that during interference trials (incongruent versus congruent),
higher activation of the vmPFC, posterior cingulate, and striatum predicted a longer
duration of self-reported abstinence (the striatum additionally predicted percent of
negative urine screens); and reduced activation of the DLPFC predicted treatment
retention (Brewer et al., 2008). In another study, a drug (cocaine) Stroop task was
administered to cocaine-dependent patients during their first week in detoxification
treatment and was used to predict cocaine use at 3-month follow-up. Dorsal ACC
activation to cocaine versus neutral words positively predicted future cocaine use
(i.e., relapse) (Marhe et al., 2013). Interestingly, the direction of correlation was op-
posite to the previous study, perhaps attributable to the task valence (emotionally
neutral in the former versus emotionally salient in the latter).
Other fMRI studies instead examined the predictive effects of task-related con-
nectivity during neutral Stroop tasks. In one study, 16 treatment-seeking cocaine-
dependent individuals and matched healthy controls completed an fMRI color-word
Stroop task (Mitchell et al., 2013). In addition to the behavioral Stroop predicting
abstinence [i.e., more interference at pretreatment correlated with better outcome,
supporting the study above (Brewer et al., 2008)], less functional connectivity among
the ventral striatum, thalamus, substantia nigra, right insula, and left hippocampus
predicted better clinical outcome (longer abstinence) (Mitchell et al., 2013). This
finding is somewhat difficult to interpret considering that the addicted individuals
had less connectivity among these regions overall than healthy controls. Neverthe-
less, this prospective finding within the addicted group is consistent with other work
showing that subcortical pathways in drug addiction are hyperconnected during
resting-state in association with a greater severity of dependence (Konova et al.,
2013); less hyperconnectivity of these subcortical structures, then, could be driving
the better treatment outcomes observed in this study. In contrast, however, in a
second connectivity study of treatment-seeking cocaine-addicted individuals, inde-

pendent component analysis (ICA) was applied to fMRI data during color-word
Stroop interference (Worhunsky et al., 2013). Here, better clinical outcome (higher
numbers of negative cocaine urine screens) was predicted by greater engagement of a
subcortical network (encompassing the thalamus, striatum, amygdala, and hippo-
campus) and a “ventral frontostriatal” network (encompassing vmPFC, ventral stri-
atum, and subgenual/rostral components of the ACC). In contrast, more weeks in
treatment were associated with reduced engagement of a “frontocingular” network
(encompassing ACC, medial PFC, and insula). Thus, additional research is needed to
reconcile inconsistencies among the studies, especially with respect to the contribu-
tion of subcortical structures.
Other studies have used bookend (pre–post) fMRI sessions to examine neural
changes as a function of treatment and/or abstinence. In one study, substance-
dependent individuals underwent fMRI during a color-word Stroop task at baseline
and follow-up, with 8 weeks of computer-assisted cognitive behavioral therapy for
substance abuse in between the two scanning sessions; nonsubstance-using control
participants also completed the Stroop task following a similar time interval. At
follow-up, the treatment-seekers showed decreased interference-related fMRI signal
in multiple brain regions including the DLPFC, ACC, IFG, and a subcortical cluster
that encompassed the midbrain and subthalamic nucleus (Devito et al., 2012). In an-
other study, treatment-seeking cocaine-addicted individuals completed a drug Stroop
task at baseline and then again at a 6-month follow-up. Results showed that midbrain
fMRI signal increased during the entire task (to drug and neutral words) from base-
line to follow-up, and this enhanced midbrain response correlated with reduced
cocaine-related choice on a simulated drug-choice paradigm (Moeller et al., 2012b).
4.4 PART 2 SUMMARY

Here, many of the behavior-only studies used drug Stroop tasks, which yielded some-
what mixed/contradictory results in predicting clinical outcome in treatment-seeking
drug-addicted individuals. When inhibition tasks were combined with neuroimaging,
prediction was generally improved. Similarly to the initiation literature, these neu-
roimaging effects generally emerged in the absence of behavioral task effects (par-
ticularly for go/no-go and stop-signal tasks) (Table 2). In contrast, the Stroop tasks
were often associated with behavioral differences (between groups, assessment time
points, etc.) (Table 2), and therefore, one cannot rule out the possibility that differ-
ential fMRI activations are attributable to differential ability of individuals to per-
form the task. Despite this potential uncertainty, however, these imaging studies
were fairly consistent in showing that clinical outcome was prospectively predicted
by the DLPFC, dorsal ACC, IFG, and regions of the basal ganglia such as the stri-
atum and midbrain. In general, although with multiple exceptions, better clinical out-
come was predicted by decreased PFC activation but enhanced subcortical
activation. The predictive effect of subcortical activation could be attributable to
recovery of dopaminergic integrity with abstinence (Volkow et al., 2001).
Nevertheless, it is important to replicate this subcortical effect in future work, both

because of the inconsistent direction of activation in these studies and because sub-
cortical activations are not as reliably reported during inhibitory control tasks in
healthy individuals.
Overall, better response inhibition and less activation during the exertion of in-
hibitory control predicted a better clinical outcome. As there is no a priori reason to
suspect that individuals with better response inhibition had a less severe addiction,
these studies suggest that better response inhibition helps individuals to refrain from
drug-taking when they are motivated to do so. An interesting variable to examine in
this regard, which was not routinely reported in these studies, is the number of quit
attempts during the course of the addiction. One could anticipate that individuals
with better response inhibition would have fewer quit attempts.

5.1 PARADIGM CONSIDERATIONS
An important future direction is to test whether there are unique neural mechanisms
underlying the ability to exert inhibitory control in a drug-related context versus a
neutral context. Insofar as inhibitory control in drug-addicted individuals is antici-
pated to be lowest upon being confronted with drugs or drug-associated stimuli
(Goldstein and Volkow, 2011), such task designs could potentially explain unique
variance in drug use outcomes—particularly since neuropsychological impairments
in drug addiction, while pervasive, are generally mild in magnitude and may require
more sensitive neuropsychological probes for their detection (Goldstein et al., 2004,
2007; Moeller et al., 2009; Woicik et al., 2009). Although drug Stroop tasks have
been deployed to predict clinical outcome in addicted individuals as reviewed above,
these studies generally have not concurrently administered a standard color-word
Stroop task for direct comparisons (e.g., drug task minus matched neutral task).
Response inhibition paradigms could also benefit from designs that enable the
parametric correlation of trial-by-trial behavioral responses with the associated neural
signals for each individual. This type of design could help reduce concerns about in-
terpretation of the fMRI effects when there are also behavioral differences between
groups or longitudinal assessments. More broadly, another interesting direction would
be to directly contrast an inhibitory control task with another demanding cognitive task
(e.g., working memory) that engages similar neural circuitry (e.g., the DLPFC). In this
way, one could test whether any cognitively demanding task predicts future drug use,
or whether there are uniquely predictive aspects of response inhibition.
5.2 EXPAND STUDY INTO MORE ADDICTIONS

Another important direction is to expand the present literature into different drug
classes. Alcohol is overrepresented in studies examining the prediction of drug
use initiation, and cocaine is overrepresented in studies examining prediction of
clinical outcome. For the former (prediction of initiation), the decision to focus on
alcohol use is justified, given the focus of these studies on adolescents and young
adults. Nevertheless, it will be important to expand this young adult longitudinal
literature into the misuse of opioid prescription medication, which has become a
paramount public health concern in recent years (Schrager et al., 2014). Moreover,
the recent legalization of marijuana in several states (e.g., Colorado and Washing-
ton) has increased concerns about underage use and misuse (Monte et al., 2015).
For the latter (prediction of outcome), it will be important to increase the number
of studies examining how response inhibition impacts clinical outcomes in other
addictions that have high public health implications (e.g., nicotine, alcohol, heroin,
methamphetamine). Beyond drug addiction, there is scant inhibitory control lon-
gitudinal research on behavioral addictions, such as gambling or internet/video
game addiction.
5.3 INDIVIDUAL DIFFERENCES

It is imperative to study addicted individuals with psychiatric comorbidities. Individ-
uals with comorbidities represent a majority of addicted individuals and are more
likely to have unmet treatment needs (Melchior et al., 2014). Another potential
modulatory variable is the presence of comorbid attention deficit/hyperactivity dis-
order (ADHD), which is associated with both the initiation of substance abuse and
impaired response inhibition (Lee et al., 2011); other externalizing symptomatology,
such as anger, could also be important to examine (Aharonovich et al., 2001).
Finally, sex differences may modulate response inhibition in drug addiction, as in-
dicated by one of the studies reviewed above (Luo et al., 2013). In further support,
in a study examining sex by substance dependence interactions on self-reported
impulsivity, female drug-addicted individuals exhibited the highest impulsivity of
all participant groupings (Perry et al., 2013). Women may also have greater difficulty
inhibiting drug use (e.g., smoking) following cue exposure (Doran, 2014).
5.4 UNDERLYING NEUROCHEMISTRY

The neurochemistry of these effects also remains to be uncovered, especially if these
results are to aid the development of innovative pharmacotherapies to treat drug ad-
diction. Dopamine is likely to play an important role, given its reported contribution
to higher-order cognitive functions that bear on self-regulation/response inhibition
inclusive of cognitive flexibility (Kehagia et al., 2010), exertion/sustaining effort
(Niv et al., 2007; Satoh et al., 2003), and motivation (Moeller et al., 2012a). Support-
ing the latter, in a preliminary sample of cocaine-addicted individuals and healthy
controls, we showed that dopamine D2 receptor availability, measured by positron
emission tomography (PET) with [11C]raclopride, correlated with fMRI midbrain re-
sponse to errors during the color-word Stroop task when cognitive resources were
presumably most depleted (during the final versus the first task repetition)
(Moeller et al., 2012a). In addition, studies administering the stop-signal tasks during
PET with [18F]fallypride in healthy individuals revealed correlations between SSRT

and D2/D3 receptor availability in the left OFC, right MFG, and right precentral gy-
rus (Albrecht et al., 2014) and the striatum (Ghahremani et al., 2012). Accordingly,
therapeutic agents that act on this system, such as the indirect dopamine agonist
methylphenidate, could be used to modulate the neural correlates of response inhi-
bition in drug addiction as indeed previously demonstrated (Goldstein et al., 2010; Li
et al., 2010; Moeller et al., 2014; Sofuoglu et al., 2013).
5.5 SUMMARY, LIMITATIONS, AND CLINICAL IMPLICATIONS

We reviewed behavioral and neuroimaging studies of response inhibition aiming to
predict longitudinal outcomes in substance abuse. We identified a larger number of
studies relevant to the prediction of clinical outcome than to the prediction of tran-
sition into substance abuse, underscoring a need for more studies that can detect
at-risk individuals before they transition to addiction. In particular, needed are
large-scale, comprehensive studies that can integrate and/or disentangle the influ-
ences of multiple and multimodal predictors related to response inhibition; the
creation of several collaborative imaging consortiums has begun to address this
crucial gap (Paus, 2010) (see results in the current review reported by Whelan
et al., 2014). These big data initiatives can also help resolve some of the inconsis-
tencies between studies, as small sample sizes are likely to represent a source of
increased variation; this concern is accentuated for the relapse prediction studies,
which as a whole had smaller sample sizes than the drug use initiation studies.
Another concern for these relapse prediction studies is the abstinence length at
the time of scanning: abstinence length was variable between the studies (ranging
from hours to weeks), and in many studies, this information was not reported
(Table 2). This variable could have crucial bearing on the capacity to exert inhib-
itory control (e.g., if one is studying participants who are experiencing acute
withdrawal symptoms and/or intense craving), or alternatively could be evidence
of individuals having already exerted inhibitory control (e.g., if one is studying
participants who have sustained abstinence for several weeks). Moreover, one
needs also to exercise a degree of caution when interpreting the results of studies
that retrospectively test for neuroimaging predictors (e.g., using the outcome, such
as relapse versus abstinence, as the basis of creating groups for a baseline neuro-
imaging analysis). This type of analysis can lead to overfitting that can inflate the
magnitude of the observed differences, a problem that has been well-articulated
elsewhere (Garavan et al., 2013).
Despite these concerns, results generally support the hypothesis that these tasks,
and their underlying neural correlates, predict important prospective outcomes. Be-
haviorally, better response inhibition generally predicted better outcomes. Neurally,
the general pattern of results was that frontal regions were less activated during the
exertion of inhibitory control in the individuals who would later become problematic
substance users. This finding of blunted frontal activation during response inhibition
References 183
is also consistent with other externalizing psychopathologies, including ADHD

(Rubia et al., 2011) and intermittent explosive disorder (Coccaro et al., 2007). Inter-
estingly, however, less activation of similar frontal regions generally predicted better
clinical outcomes when the context was sustaining abstinence.
These results have important clinical implications. Although these results cannot
illuminate causal relationships between variables, longitudinal prediction constitutes
an improvement over cross-sectional studies and can support the important conclu-
sion that response inhibition deficits could be targeted for intervention to improve
future outcomes. These could include targeted cognitive–behavioral exercises, pos-
sibly in combination with pharmacotherapy and/or individualized neurofeedback.
These types of interventions can help address the vital public health goals of iden-
tifying the young individuals most likely to progress from recreational to problematic
substance use, and identifying the addicted individuals most likely to relapse after
beginning treatment or abstinence. Individuals with reduced inhibitory control could
be selected for additional therapeutic/interventional resources to produce better
drug-related outcomes.
ACKNOWLEDGMENTS
This work was supported by the National Institute on Drug Abuse (to S.J.M.:
1K01DA037452), and by seed grants from the Icahn School of Medicine at Mount Sinai
and the Mount Sinai Brain Imaging Center (to S.J.M., N.A.K., and R.Z.G.). We thank Gabriela
Gan, Rebecca Preston-Campbell, and Anna B. Konova for helpful suggestions on concepts
presented in this chapter.
Disclosure/Conflict of Interest: None declared.
REFERENCES
Aharonovich, E., Nguyen, H.T., Nunes, E.V., 2001. Anger and depressive states among
treatment-seeking drug abusers: testing the psychopharmacological specificity hypothesis.
Am. J. Addict. 10 (4), 327–334.
Albrecht, D.S., Kareken, D.A., Christian, B.T., Dzemidzic, M., Yoder, K.K., 2014. Cortical
dopamine release during a behavioral response inhibition task. Synapse 68 (6),
266–274. doi:http://dx.doi.org/10.1002/syn.21736.
tex: one decade on. Trends Cogn. Sci. 18 (4), 177–185. doi:http://dx.doi.org/10.1016/j.
tics.2013.12.003.
Bari, A., Robbins, T.W., 2013. Inhibition and impulsivity: behavioral and neural basis of
response control. Prog. Neurobiol. 108, 44–79. doi:http://dx.doi.org/10.1016/j.pneurobio.
2013.06.005.
Beltz, A.M., Gates, K.M., Engels, A.S., Molenaar, P.C., Pulido, C., Turrisi, R., et al., 2013.
Changes in alcohol-related brain networks across the first year of college: a prospective
pilot study using fMRI effective connectivity mapping. Addict. Behav. 38 (4),
2052–2059. doi:http://dx.doi.org/10.1016/j.addbeh.2012.12.023.
Berkman, E.T., Falk, E.B., Lieberman, M.D., 2011. In the trenches of real-world self-control:
neural correlates of breaking the link between craving and smoking. Psychol. Sci. 22 (4),
498–506. doi:http://dx.doi.org/10.1177/0956797611400918.
treatment brain activation during Stroop task is associated with outcomes in cocaine-
dependent patients. Biol. Psychiatry 64 (11), 998–1004. doi:http://dx.doi.org/10.1016/j.
biopsych.2008.05.024.
Carpenter, K.M., Schreiber, E., Church, S., McDowell, D., 2006. Drug Stroop performance:
relationships with primary substance of use and treatment outcome in a drug-dependent
outpatient sample. Addict. Behav. 31 (1), 174–181. doi:http://dx.doi.org/10.1016/j.
addbeh.2005.04.012.
Carpenter, K.M., Martinez, D., Vadhan, N.P., Barnes-Holmes, D., Nunes, E.V., 2012. Mea-
sures of attentional bias and relational responding are associated with behavioral treatment
outcome for cocaine dependence. Am. J. Drug Alcohol Abuse 38 (2), 146–154. doi:http://
dx.doi.org/10.3109/00952990.2011.643986.
Chambers, C.D., Garavan, H., Bellgrove, M.A., 2009. Insights into the neural basis of response
inhibition from cognitive and clinical neuroscience. Neurosci. Biobehav. Rev. 33 (5),
631–646. doi:http://dx.doi.org/10.1016/j.neubiorev.2008.08.016.
Cieslik, E.C., Mueller, V.I., Eickhoff, C.R., Langner, R., Eickhoff, S.B., 2015. Three key re-
gions for supervisory attentional control: evidence from neuroimaging meta-analyses.
Neurosci. Biobehav. Rev. 48C, 22–34. doi:http://dx.doi.org/10.1016/j.neubiorev.2014.11.003.
Coccaro, E.F., McCloskey, M.S., Fitzgerald, D.A., Phan, K.L., 2007. Amygdala and orbito-
frontal reactivity to social threat in individuals with impulsive aggression. Biol. Psychiatry
62 (2), 168–178. doi:http://dx.doi.org/10.1016/j.biopsych.2006.08.024.
Cox, W.M., Hogan, L.M., Kristian, M.R., Race, J.H., 2002. Alcohol attentional bias as a pre-
dictor of alcohol abusers’ treatment outcome. Drug Alcohol Depend. 68 (3), 237–243.
Cox, W.M., Fadardi, J.S., Pothos, E.M., 2006. The addiction-Stroop test: theoretical consid-
erations and procedural recommendations. Psychol. Bull. 132 (3), 443–476.
Devito, E.E., Worhunsky, P.D., Carroll, K.M., Rounsaville, B.J., Kober, H., Potenza, M.N.,
2012. A preliminary study of the neural effects of behavioral therapy for substance use
disorders. Drug Alcohol Depend. 122 (3), 228–235. doi:http://dx.doi.org/10.1016/j.
Doran, N., 2014. Sex differences in smoking cue reactivity: craving, negative affect, and pref-
erence for immediate smoking. Am. J. Addict. 23 (3), 211–217. doi:http://dx.doi.org/
10.1111/j.1521-0391.2014.12094.x.
Egner, T., Etkin, A., Gale, S., Hirsch, J., 2008. Dissociable neural systems resolve conflict
from emotional versus nonemotional distracters. Cereb. Cortex 18 (6), 1475–1484. doi:
http://dx.doi.org/10.1093/cercor/bhm179.
Fernie, G., Peeters, M., Gullo, M.J., Christiansen, P., Cole, J.C., Sumnall, H., Field, M., 2013.
Multiple behavioural impulsivity tasks predict prospective alcohol involvement in adoles-
cents. Addiction 108 (11), 1916–1923. doi:http://dx.doi.org/10.1111/add.12283.
Filbey, F.M., Claus, E.D., Morgan, M., Forester, G.R., Hutchison, K., 2012. Dopaminergic
genes modulate response inhibition in alcohol abusing adults. Addict. Biol. 17 (6),
1046–1056. doi:http://dx.doi.org/10.1111/j.1369-1600.2011.00328.x.
Fineberg, N.A., Chamberlain, S.R., Goudriaan, A.E., Stein, D.J., Vanderschuren, L.J.,
Gillan, C.M., et al., 2014. New developments in human neurocognition: clinical, genetic,
and brain imaging correlates of impulsivity and compulsivity. CNS Spectr. 19 (1), 69–89.
doi:http://dx.doi.org/10.1017/s1092852913000801.
References 185
Garavan, H., Brennan, K.L., Hester, R., Whelan, R., 2013. The neurobiology of successful
abstinence. Curr. Opin. Neurobiol. 23 (4), 668–674. doi:http://dx.doi.org/10.1016/j.
conb.2013.01.029.
Ghahremani, D.G., Lee, B., Robertson, C.L., Tabibnia, G., Morgan, A.T., De Shetler, N., et al.,
2012. Striatal dopamine D(2)/D(3) receptors mediate response inhibition and related ac-
tivity in frontostriatal neural circuitry in humans. J. Neurosci. 32 (21), 7316–7324. doi:
http://dx.doi.org/10.1523/jneurosci.4284-11.2012.
Goldstein, R.Z., Volkow, N.D., 2011. Dysfunction of the prefrontal cortex in addiction: neu-
roimaging findings and clinical implications. Nat. Rev. Neurosci. 12 (11), 652–669. doi:
http://dx.doi.org/10.1038/nrn3119.
Goldstein, R.Z., Leskovjan, A.C., Hoff, A.L., Hitzemann, R., Bashan, F., Khalsa, S.S., et al.,
2004. Severity of neuropsychological impairment in cocaine and alcohol addiction: asso-
ciation with metabolism in the prefrontal cortex. Neuropsychologia 42 (11), 1447–1458.
Goldstein, R.Z., Woicik, P.A., Lukasik, T., Maloney, T., Volkow, N.D., 2007. Drug fluency: a
potential marker for cocaine use disorders. Drug Alcohol Depend. 89 (1), 97–101.
Goldstein, R.Z., Woicik, P.A., Maloney, T., Tomasi, D., Alia-Klein, N., Shan, J., Volkow, N.D.,
2010. Oral methylphenidate normalizes cingulate activity in cocaine addiction during a
salient cognitive task. Proc. Natl. Acad. Sci. USA 107 (38), 16667–16672. doi:http://dx.
doi.org/10.1073/pnas.1011455107.
Hardee, J.E., Weiland, B.J., Nichols, T.E., Welsh, R.C., Soules, M.E., Steinberg, D.B., et al.,
2014. Development of impulse control circuitry in children of alcoholics. Biol. Psychiatry
Heitzeg, M.M., Nigg, J.T., Hardee, J.E., Soules, M., Steinberg, D., Zubieta, J.K., Zucker, R.A.,
2014. Left middle frontal gyrus response to inhibitory errors in children prospectively pre-
dicts early problem substance use. Drug Alcohol Depend. 141, 51–57. doi:http://dx.doi.
org/10.1016/j.drugalcdep.2014.05.002.
Heitzeg, M.M., Cope, L.M., Martz, M.E., Hardee, J.E., 2015. Neuroimaging risk markers for
substance abuse: recent findings on inhibitory control and reward system functioning.
Curr. Addict. Rep. 2 (2), 91–103.
Hester, R., Nestor, L., Garavan, H., 2009. Impaired error awareness and anterior cingulate cor-
tex hypoactivity in chronic cannabis users. Neuropsychopharmacology 34, 2450–2458.
Jakubczyk, A., Klimkiewicz, A., Kopera, M., Krasowska, A., Wrzosek, M., Matsumoto, H.,
et al., 2013. The CC genotype in the T102C HTR2A polymorphism predicts relapse in
individuals after alcohol treatment. J. Psychiatr. Res. 47 (4), 527–533. doi:http://dx.doi.
org/10.1016/j.jpsychires.2012.12.004.
neural reactivity to drug cues in addiction: a survey of human neuroimaging studies. Neu-
rosci. Biobehav. Rev. 38, 1–16. doi:http://dx.doi.org/10.1016/j.neubiorev.2013.10.013.
Kalivas, P.W., Volkow, N.D., 2005. The neural basis of addiction: a pathology of motivation
and choice. Am. J. Psychiatry 162 (8), 1403–1413.
Kehagia, A.A., Murray, G.K., Robbins, T.W., 2010. Learning and cognitive flexibility: fron-
tostriatal function and monoaminergic modulation. Curr. Opin. Neurobiol. 20 (2),
199–204. doi:http://dx.doi.org/10.1016/j.conb.2010.01.007.
Kerns, J.G., Cohen, J.D., MacDonald 3rd, A.W., Cho, R.Y., Stenger, V.A., Carter, C.S., 2004.
Anterior cingulate conflict monitoring and adjustments in control. Science 303 (5660),
1023–1026.
Konova, A.B., Moeller, S.J., Tomasi, D., Volkow, N.D., Goldstein, R.Z., 2013. Effects of
methylphenidate on resting-state functional connectivity of the mesocorticolimbic
dopamine pathways in cocaine addiction. JAMA Psychiatry 70 (8), 857–868. doi:http://dx.

doi.org/10.1001/jamapsychiatry.2013.1129.
Lee, S.S., Humphreys, K.L., Flory, K., Liu, R., Glass, K., 2011. Prospective association of
childhood attention-deficit/hyperactivity disorder (ADHD) and substance use and
abuse/dependence: a meta-analytic review. Clin. Psychol. Rev. 31 (3), 328–341. doi:
http://dx.doi.org/10.1016/j.cpr.2011.01.006.
Li, C.S., Morgan, P.T., Matuskey, D., Abdelghany, O., Luo, X., Chang, J.L., Malison, R.T.,
2010. Biological markers of the effects of intravenous methylphenidate on improving
inhibitory control in cocaine-dependent patients. Proc. Natl. Acad. Sci. USA 107 (32),
14455–14459.
Luijten, M., Machielsen, M.W., Veltman, D.J., Hester, R., de Haan, L., Franken, I.H., 2014.
Systematic review of ERP and fMRI studies investigating inhibitory control and error pro-
cessing in people with substance dependence and behavioural addictions. J. Psychiatry
Neurosci. 39 (3), 149–169.
Luo, X., Zhang, S., Hu, S., Bednarski, S.R., Erdman, E., Farr, O.M., et al., 2013. Error proces-
sing and gender-shared and -specific neural predictors of relapse in cocaine dependence.
Brain 136 (Pt 4), 1231–1244. doi:http://dx.doi.org/10.1093/brain/awt040.
MacLeod, C.M., 1991. Half a century of research on the Stroop effect: an integrative review.
Psychol. Bull. 109 (2), 163–203.
Mahmood, O.M., Goldenberg, D., Thayer, R., Migliorini, R., Simmons, A.N., Tapert, S.F., 2013.
Adolescents’ fMRI activation to a response inhibition task predicts future substance use.
Addict. Behav. 38 (1), 1435–1441. doi:http://dx.doi.org/10.1016/j.addbeh.2012.07.012.
Marhe, R., Luijten, M., van de Wetering, B.J., Smits, M., Franken, I.H., 2013. Individual dif-
ferences in anterior cingulate activation associated with attentional bias predict cocaine
use after treatment. Neuropsychopharmacology 38 (6), 1085–1093. doi:http://dx.doi.
org/10.1038/npp.2013.7.
Melchior, M., Prokofyeva, E., Younes, N., Surkan, P.J., Martins, S.S., 2014. Treatment for
illegal drug use disorders: the role of comorbid mood and anxiety disorders. BMC Psychi-
atry 14, 89. doi:http://dx.doi.org/10.1186/1471-244x-14-89.
Mitchell, M.R., Balodis, I.M., Devito, E.E., Lacadie, C.M., Yeston, J., Scheinost, D., et al.,
2013. A preliminary investigation of Stroop-related intrinsic connectivity in cocaine de-
pendence: associations with treatment outcomes. Am. J. Drug Alcohol Abuse 39 (6),
392–402. doi:http://dx.doi.org/10.3109/00952990.2013.841711.
Moeller, S.J., Goldstein, R.Z., 2014. Impaired self-awareness in human addiction: deficient
attribution of personal relevance. Trends Cogn. Sci. 18 (12), 635–641. doi:http://dx.doi.
org/10.1016/j.tics.2014.09.003.
Moeller, S.J., Maloney, T., Parvaz, M.A., Dunning, J.P., Alia-Klein, N., Woicik, P.A., et al.,
2009. Enhanced choice for viewing cocaine pictures in cocaine addiction. Biol. Psychiatry
Moeller, S.J., Tomasi, D., Honorio, J., Volkow, N.D., Goldstein, R.Z., 2012a. Dopaminergic
involvement during mental fatigue in health and cocaine addiction. Transl. Psychiatry
2, e176. doi:http://dx.doi.org/10.1038/tp.2012.110.
Moeller, S.J., Tomasi, D., Woicik, P.A., Maloney, T., Alia-Klein, N., Honorio, J., et al., 2012b.
Enhanced midbrain response at 6-month follow-up in cocaine addiction, association with
reduced drug-related choice. Addict. Biol. 17 (6), 1013–1025. doi:http://dx.doi.org/
10.1111/j.1369-1600.2012.00440.x.
Moeller, S.J., Honorio, J., Tomasi, D., Parvaz, M.A., Woicik, P.A., Volkow, N.D.,
Goldstein, R.Z., 2014. Methylphenidate enhances executive function and optimizes
References 187
prefrontal function in both health and cocaine addiction. Cereb. Cortex 24 (3), 643–653.
doi:http://dx.doi.org/10.1093/cercor/bhs345.
Monte, A.A., Zane, R.D., Heard, K.J., 2015. The implications of marijuana legalization in Col-
orado. JAMA 313 (3), 241–242. doi:http://dx.doi.org/10.1001/jama.2014.17057.
Nigg, J.T., Wong, M.M., Martel, M.M., Jester, J.M., Puttler, L.I., Glass, J.M., et al., 2006.
Poor response inhibition as a predictor of problem drinking and illicit drug use in ado-
lescents at risk for alcoholism and other substance use disorders. J. Am. Acad. Child
Adolesc. Psychiatry 45 (4), 468–475. doi:http://dx.doi.org/10.1097/01.chi.0000199028.
76452.a9.
Niv, Y., Daw, N.D., Joel, D., Dayan, P., 2007. Tonic dopamine: opportunity costs and the con-
trol of response vigor. Psychopharmacology (Berl) 191 (3), 507–520.
Norman, A.L., Pulido, C., Squeglia, L.M., Spadoni, A.D., Paulus, M.P., Tapert, S.F., 2011.
Neural activation during inhibition predicts initiation of substance use in adolescence.
Drug Alcohol Depend. 119 (3), 216–223. doi:http://dx.doi.org/10.1016/j.drugalcdep.2011.
06.019.
Paus, T., 2010. Population neuroscience: why and how. Hum. Brain Mapp. 31 (6), 891–903.
doi:http://dx.doi.org/10.1002/hbm.21069.
Peeters, M., Monshouwer, K., van de Schoot, R.A., Janssen, T., Vollebergh, W.A., Wiers, R.W.,
2013. Automatic processes and the drinking behavior in early adolescence: a prospective
study. Alcohol. Clin. Exp. Res. 37 (10), 1737–1744. doi:http://dx.doi.org/10.1111/
acer.12156.
Perry, R.I., Krmpotich, T., Thompson, L.L., Mikulich-Gilbertson, S.K., Banich, M.T.,
Tanabe, J., 2013. Sex modulates approach systems and impulsivity in substance depen-
dence. Drug Alcohol Depend. 133 (1), 222–227. doi:http://dx.doi.org/10.1016/j.
Prisciandaro, J.J., Myrick, H., Henderson, S., McRae-Clark, A.L., Brady, K.T., 2013. Prospec-
tive associations between brain activation to cocaine and no-go cues and cocaine relapse.
Drug Alcohol Depend. 131 (1-2), 44–49. doi:http://dx.doi.org/10.1016/j.drugalcdep.
2013.04.008.
Rubia, K., Halari, R., Cubillo, A., Smith, A.B., Mohammad, A.M., Brammer, M., Taylor, E.,
2011. Methylphenidate normalizes fronto-striatal underactivation during interference
inhibition in medication-naive boys with attention-deficit hyperactivity disorder.
Neuropsychopharmacology 36 (8), 1575–1586. doi:http://dx.doi.org/10.1038/npp.2011.30.
Satoh, T., Nakai, S., Sato, T., Kimura, M., 2003. Correlated coding of motivation and outcome
of decision by dopamine neurons. J. Neurosci. 23 (30), 9913–9923.
Schmaal, L., Joos, L., Koeleman, M., Veltman, D.J., van den Brink, W., Goudriaan, A.E.,
2013. Effects of modafinil on neural correlates of response inhibition in alcohol-dependent
patients. Biol. Psychiatry 73 (3), 211–218. doi:http://dx.doi.org/10.1016/j.biopsych.2012.
06.032.
Schrager, S.M., Kecojevic, A., Silva, K., Jackson Bloom, J., Iverson, E., Lankenau, S.E., 2014.
Correlates and consequences of opioid misuse among high-risk young adults. J. Addict.
2014, 156954. doi:http://dx.doi.org/10.1155/2014/156954.
Smith, D.G., Ersche, K.D., 2014. Using a drug-word Stroop task to differentiate recreational
from dependent drug use. CNS Spectr. 19 (3), 247–255. doi:http://dx.doi.org/10.1017/
s1092852914000133.
Smith, J.L., Mattick, R.P., Jamadar, S.D., Iredale, J.M., 2014. Deficits in behavioural inhibi-
tion in substance abuse and addiction: a meta-analysis. Drug Alcohol Depend. 145, 1–33.
doi:http://dx.doi.org/10.1016/j.drugalcdep.2014.08.009.
Sofuoglu, M., Devito, E.E., Waters, A.J., Carroll, K.M., 2013. Cognitive enhancement as a
treatment for drug addictions. Neuropharmacology 64 (1), 452–463. doi:http://dx.doi.
org/10.1016/j.neuropharm.2012.06.021.
Verbruggen, F., Logan, G.D., 2008. Response inhibition in the stop-signal paradigm. Trends
Cogn. Sci. 12 (11), 418–424. doi:http://dx.doi.org/10.1016/j.tics.2008.07.005.
Verdejo-Garcia, A., Betanzos-Espinosa, P., Lozano, O.M., Vergara-Moragues, E., Gonzalez-
Saiz, F., Fernandez-Calderon, F., et al., 2012. Self-regulation and treatment retention in
cocaine dependent individuals: a longitudinal study. Drug Alcohol Depend. 122 (1-2),
142–148. doi:http://dx.doi.org/10.1016/j.drugalcdep.2011.09.025.
Volkow, N.D., Chang, L., Wang, G.J., Fowler, J.S., Franceschi, D., Sedler, M., Logan, J.,
2001. Loss of dopamine transporters in methamphetamine abusers recovers with pro-
tracted abstinence. J. Neurosci. 21 (23), 9414–9418.
Wetherill, R.R., Squeglia, L.M., Yang, T.T., Tapert, S.F., 2013. A longitudinal examination of
adolescent response inhibition: neural differences before and after the initiation of heavy
drinking. Psychopharmacology (Berl) 230 (4), 663–671. doi:http://dx.doi.org/10.1007/
s00213-013-3198-2.
Whelan, R., Watts, R., Orr, C.A., Althoff, R.R., Artiges, E., Banaschewski, T., et al., 2014.
Neuropsychosocial profiles of current and future adolescent alcohol misusers. Nature
512 (7513), 185–189. doi:http://dx.doi.org/10.1038/nature13402.
Woicik, P.A., Moeller, S.J., Alia-Klein, N., Maloney, T., Lukasik, T.M., Yeliosof, O., et al.,
2009. The neuropsychology of cocaine addiction: recent cocaine use masks impairment.
Wong, M.M., Brower, K.J., Nigg, J.T., Zucker, R.A., 2010. Childhood sleep problems, re-
sponse inhibition, and alcohol and drug outcomes in adolescence and young adulthood.
Alcohol. Clin. Exp. Res. 34 (6), 1033–1044. doi:http://dx.doi.org/10.1111/j.1530-
0277.2010.01178.x.
Worhunsky, P.D., Stevens, M.C., Carroll, K.M., Rounsaville, B.J., Calhoun, V.D.,
Pearlson, G.D., Potenza, M.N., 2013. Functional brain networks associated with cognitive
control, cocaine dependence, and treatment outcome. Psychol. Addict. Behav. 27 (2),
477–488. doi:http://dx.doi.org/10.1037/a0029092.
CHAPTER
Neuroscience of nicotine
for addiction medicine:
novel targets for smoking
cessation medications
10
Manoranjan S. D’Souza1
Department of Biomedical and Pharmaceutical Sciences, The Raabe College of Pharmacy,
Ohio Northern University, Ada, OH, USA
1
Abstract
Morbidity and mortality associated with tobacco smoking constitutes a significant burden on
healthcare budgets all over the world. Therefore, promoting smoking cessation is an important
goal of health professionals and policy makers throughout the world. Nicotine is a major psy-
choactive component in tobacco that is largely responsible for the widespread addiction to to-
bacco. A majority of the currently available FDA-approved smoking cessation medications act
via neuronal nicotinic receptors. These medications are effective in approximately half of all
the smokers, who want to quit and relapse among abstinent smokers continues to be high. In
addition to relapse among abstinent smokers, unpleasant effects associated with nicotine with-
drawal are a major motivational factor in continued tobacco smoking. Over the last two de-
cades, animal studies have helped in identifying several neural substrates that are involved in
nicotine-dependent behaviors including those associated with nicotine withdrawal and relapse
to tobacco smoking. In this review, first the role of specific brain regions/circuits that are in-
volved in nicotine dependence will be discussed. Next, the review will describe the role of
specific nicotinic receptor subunits in nicotine dependence. Finally, the review will discuss
the role of classical neurotransmitters (dopamine, serotonin, noradrenaline, glutamate, and
g-aminobutyric acid) as well as endogenous opioid and endocannabinoid signaling in nicotine
dependence. The nicotinic and nonnicotinic neural substrates involved in nicotine-dependent
behaviors can serve as possible targets for future smoking cessation medications.
Keywords
Glutamate, GABA, Nicotine withdrawal, Reinstatement, Opioids, Endocannabinoids, Seroto-
nin, Habenula, Nucleus accumbens, Interpeduncular nucleus

191
192 CHAPTER 10 Neuroscience of nicotine for addiction medicine
Abbreviations
AMPA amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate
CRF corticotropin-releasing factor
FAAH fatty acid amide hydrolase
GABA g-aminobutyric acid
ICSS intracranial self-stimulation
mGlu metabotropic glutamate
NAcc nucleus accumbens
nAChRs nicotinic acetylcholine receptors
NMDA N-methyl-D-aspartate
nor-BNI norbinaltorphimine
PAMs positive allosteric modulators
VTA ventral tegmental area
1 INTRODUCTION
Currently, there are approximately 1.3 billion adult smoker’s worldwide, making
tobacco addiction one of the most prevalent addictions all over the world. Impor-
tantly, mortality attributed to tobacco smoking is estimated to rise to approxi-
mately 8 million by 2030 (WHO, 2011). Cessation of tobacco smoking can
reverse some of the adverse health outcomes associated with tobacco smoking
(Fagerstrom, 2002). Although a significant number of smokers are willing to quit,
few succeed without professional help. In fact, most smokers, who attempt to quit
on their own without professional help, will relapse within the first 6 months
(Hughes et al., 2004).
Nicotine is the major psychoactive component of tobacco smoke (Stolerman
and Jarvis, 1995). The effects of nicotine are mediated by neuronal nicotinic
acetylcholine receptors (nAChRs) and current first-line Food and Drug Administra-
tion (FDA)-approved smoking cessation medications such as varenicline and nicotine
replacement therapies target these nAChRs (Nides, 2008; Rennard and Daughton,
2014; see Table 1). However, these FDA-approved medications are not effective in
all smokers who express a desire to quit. Thus, to improve the overall smoking
cessation rates, it is imperative to identify neurobiological substrates that play a role
in continued nicotine seeking. In this review, the different phases of nicotine depen-
dence will be discussed. In addition, the review will describe specific neurobiological
substrates that play a role in continued nicotine seeking and may serve as targets for
new smoking cessation medications and improve quit rates among smokers.
2 PHASES OF NICOTINE DEPENDENCE

The reinforcing effects of nicotine play an important role in the initiation and main-
tenance of tobacco smoking in humans and nicotine seeking in animals. In humans,
nicotine intake through tobacco smoking produces a pleasurable rush, mild euphoria,
3 Neurocircuitry underlying the development of nicotine dependence 193
Table 1 FDA-Approved Smoking Cessation Medications and Their Molecular

Mechanism of Action
Place in Target Molecular Mechanism
Therapy Receptor Drug of Action
First-line Nicotinic Nicotine replacement Stimulation of nicotinic

products (gum, lozenge, acetylcholine receptors
patch, nasal spray, inhaler) (nAChRs)
Varenicline Partial agonist of a4b2 nAChRs
Nicotinic Bupropion Weak inhibitor of dopamine/
and noradrenaline uptake
nonnicotinic transporters, nAChR
antagonist?
Second- Nonnicotinic Clonidine a2-adrenergic agonist
line Nortriptyline Inhibitor of noradrenaline
uptake transporters
increased arousal, decreased fatigue, and relaxation (Henningfield et al., 1985). More
importantly, nicotine-dependent smokers, who quit smoking, experience unpleasant
affective effects such as depressed mood, anhedonia, dysphoria, anxiety, irritability,
difficulty in concentrating, and craving (Shiffman and Jarvik, 1976). In addition, some
smokers may develop mild “physical” or somatic withdrawal manifestations such as
bradycardia, insomnia, gastrointestinal discomfort, and weight gain (Hughes et al.,
1991). These unpleasant effects are mediated by nicotine-induced neuroadaptations
at distinct sites/nuclei in the brain (see below). Like in humans, withdrawal of nicotine
in nicotine-dependent animals produces somatic and affective disturbances (see
Table 2). Abstinent smokers often succumb to intense cravings and reinitiate smoking,
which is termed as relapse. Relapse often occurs in response to stress, nicotine/tobacco
smoke, and/or environmental stimuli associated with nicotine (Carmody, 1992). In
animals too, stress, nicotine and nicotine-associated cues, and contexts result in rein-
statement of nicotine seeking after a period of nicotine withdrawal and extinction
training (Shaham et al., 2003; Stoker and Markou, 2015; see Table 2). Overall, the
unpleasant effects associated with nicotine withdrawal and relapse play an important
role in continued nicotine seeking. A description of animal models used to study the
neurobiology of nicotine withdrawal and relapse to nicotine seeking in humans is
described in Table 2. The next sections will describe the advances in our understanding
of the neural mechanisms underlying the unpleasant effects of nicotine withdrawal
and relapse to nicotine seeking using animal models.
3 NEUROCIRCUITRY UNDERLYING THE DEVELOPMENT

OF NICOTINE DEPENDENCE
The reinforcing effects of nicotine are mediated by the mesocorticolimbic dopami-
nergic neurons, which originate in the ventral tegmental area (VTA) and project to
several cortical and subcortical sites including the prefrontal cortex (PFC),
Table 2 Animal Models Commonly Used to Assess Different Nicotine-Dependent Behaviors
Phase of Nicotine-
Nicotine Dependent References
Dependence Behavior Model Description Data Interpretation (Example)
Nicotine Somatic Somatic signs of Animals are first made During withdrawal from Jackson
withdrawal withdrawal nicotine withdrawal dependent on nicotine using nicotine, nicotine-dependent et al. (2013)
effects subcutaneously implanted animals show somatic signs,
osmotic minipumps over a which include rearing, jumping,
period of time (7 days–4 weeks) wet-dog shakes, scratching,
and then subsequently nicotine front paw tremors, ptosis,
withdrawal is induced by abdominal constrictions,
removal of the osmotic pumps chewing, teeth chattering, and
(spontaneous withdrawal) or piloerection. Nicotine-
administration of a nicotinic dependent animals show more
receptor antagonist pronounced and significantly
(precipitated withdrawal). greater number of nicotine
Animals are observed for signs withdrawal-associated somatic
of nicotine withdrawal. signs compared to saline-
Withdrawal effects are treated animals
compared between nicotine-
and saline-treated (control)
animals. The somatic signs
occurring as a result of nicotine
withdrawal are scored by an
independent observer
Affective Nicotine Animals are surgically Elevation of reward thresholds Epping-
(anhedonia- withdrawal- implanted with electrodes compared to baseline in Jordan et al.
like state) induced directed at the medial forebrain nicotine-dependent animals (1998)
anhedonia-like bundle/lateral hypothalamus. during nicotine withdrawal is
state using Animals are subsequently indicative of development of an
intracranial self- trained to self-administer an aversive anhedonia-like state in
stimulation (ICSS) electric current to the brain over animals
a wide range of intensities.
Once the animals are trained, a
reward threshold is determined
for each animal. Reward
threshold is defined as the
minimum current that is
perceived as rewarding by the
animal. Animals are then made
dependent on nicotine using
osmotic minipumps as
described above. Reward
thresholds during nicotine
withdrawal are compared to
baseline reward thresholds of
the animals in a nicotine-
dependent state. Reward
thresholds are also compared
between nicotine- and saline-
treated animals
Affective Nicotine Animals are made dependent During nicotine withdrawal, Jackson
(anxiety-like withdrawal- on nicotine using osmotic nicotine-dependent animals et al. (2009)
state) induced anxiety- minipumps as described compared to saline-treated
like state using the above. Nicotine withdrawal is animals spend significantly less
elevated plus maze induced either by administering time in the open arm and
a nicotinic receptor antagonist demonstrate fewer open arm
or by removing the nicotine entries. Together, these
pumps. During withdrawal from behaviors indicate the
nicotine, animals are placed in development of an anxiety-like
an elevated plus maze state
Continued
Table 2 Animal Models Commonly Used to Assess Different Nicotine-Dependent Behaviors—cont’d
Phase of Nicotine-
consisting of two open arms
and two closed arms. Time
spent by the animals in the
open arm and number of entries
into the open from the closed
arm are compared between
animals withdrawing from
nicotine versus saline-treated
animals (control)
Affective Nicotine Animals are made dependent Nicotine-dependent animals Jackson
(generalized withdrawal- on nicotine using compared to saline-treated et al. (2009)
aversion) induced aversive subcutaneously implanted animals spend significantly less and Shram
state using osmotic minipumps. Several time in the compartment et al. (2008)
conditioned place days after pump implantation associated with the nicotinic
aversion (CPA) (at least 7 days; sometimes up receptor antagonist indicating
to 14 days), animals are the development of CPA
conditioned using two distinct
environments/compartments.
During the conditioning
procedure, animals are
pretreated with the nicotinic
receptor antagonist and placed
in one of the compartments.
During the next conditioning
session, animals are pretreated
with saline (control) and placed
in a distinct compartment. The
rationale behind this procedure
is that animals begin to
associate the aversive effects of
nicotine withdrawal induced via
administration of the nicotinic
receptor antagonist with the
specific compartment they are
confined to. The number of
conditioning sessions can vary
depending on the study. On the
test day, animals are given
access to both compartments,
and time spent by the animals in
the compartment associated
with the nicotinic receptor
antagonist is compared to the
time spent by the animals in the
saline-associated
compartment
Relapse Reinstatement Cue-induced In this model, animals are Lever responding during the D’Souza and
of nicotine reinstatement of surgically prepared with cue-induced reinstatement Markou
seeking nicotine seeking intravenous catheters and are session is significantly greater (2014)
trained using operant boxes to than lever responding during
self-administer nicotine by the last day of extinction
pressing a lever (acquisition of training, indicating cue-induced
self-administration). Once the reinstatement of nicotine
animals have demonstrated seeking
stable nicotine self-
administration behavior over
3–4 weeks, animals undergo
extinction training. During
extinction training, animals are
placed in the same operant
boxes with access to the lever,
Continued
Table 2 Animal Models Commonly Used to Assess Different Nicotine-Dependent Behaviors—cont’d
Phase of Nicotine-
but lever pressing does not
result in delivery of nicotine or
cues associated with nicotine.
Animals show decreased lever
responding during extinction
training. Finally, during the
reinstatement session, animals
are presented with cues
associated with nicotine and
the lever, which results in
increased lever responding
which is termed as
reinstatement of nicotine
seeking. Lever presses during
the reinstatement session
results in presentation of cues
associated with nicotine but no
nicotine delivery
Stress-induced In this procedure, the Lever responding during the Grella et al.
reinstatement of acquisition of nicotine self- stress-induced reinstatement (2014) and Qi
nicotine seeking administration and extinction session is significantly greater et al. (2015)
training are similar to that used than lever responding during
in the cue-induced the last day of extinction
reinstatement procedure. training, indicating stress-
However, prior to the induced reinstatement of
reinstatement session, animals nicotine seeking
are first subjected to stress
using footshocks or yohimbine
(an a2-adrenergic antagonist)
and then placed in the operant
chamber with access to the
lever. Lever presses during the
reinstatement session results in
presentation of cues associated
with nicotine but no nicotine
delivery
Nicotine-induced In this procedure, the Lever responding during the Forget et al.
reinstatement of acquisition of nicotine self- nicotine-induced reinstatement (2009)
nicotine seeking administration and extinction session is significantly greater
training are similar to that used than lever responding during
in the cue-induced the last day of extinction
reinstatement procedure. training, indicating nicotine-
However, either prior or during induced reinstatement of
the reinstatement session, nicotine seeking
animals are administered a
single injection of nicotine and
then given access to the lever.
Lever presses during the
reinstatement session results in
presentation of cues associated
with nicotine but no nicotine
delivery
hippocampus, habenula, nucleus accumbens (NAcc), and amygdala (De Biasi and
Dani, 2011; Koob and Volkow, 2010; Picciotto and Mineur, 2014). The activity
of these mesocorticolimbic dopaminergic neurons is regulated by reciprocal gluta-
matergic projections from the PFC, amygdala, lateral hypothalamus, and habenula
(Grace et al., 2007; Watabe-Uchida et al., 2012). In addition, the mesocorticolimbic
dopaminergic neurons receive inhibitory g-aminobutyric acid (GABA) projections
from the NAcc, rostromedial tegmental nucleus, and local circuit GABA neurons
(Geisler and Zahm, 2005). The mesocorticolimbic dopamine neurons also receive
cholinergic afferents from the pedunculopontine tegmentum and lateral dorsal teg-
mentum (Jhou et al., 2009).
The withdrawal effects of nicotine are mediated by changes in dopamine levels in
mesocorticolimbic brain sites such as the NAcc. Withdrawal of nicotine decreased
dopamine levels in the NAcc compared to baseline in nicotine-dependent rats,
possibly due to increased expression of the dopamine uptake transporter
(Hadjiconstantinou et al., 2011; Hildebrand et al., 1998). Interestingly, the decrease
in NAcc dopamine levels after administration of the nAChR antagonist mecamyl-
amine to nicotine-dependent rats was more pronounced in adolescent rats compared
to adult rats, suggesting that the mesocorticolimbic dopamine system in adolescent
rats may be more susceptible to neuroadaptive changes compared to adult rats
(Natividad et al., 2009). Nicotine withdrawal also resulted in increased expression
of corticotrophin-releasing hormone mRNA in the mesocorticolimbic dopaminergic
neurons located in the posterior VTA (Grieder et al., 2014). Furthermore, the same
study showed that blockade of corticotropin-releasing factor (CRF) 1 receptors in the
posterior VTA in mice attenuated the unpleasant affective effects associated with
nicotine withdrawal. In addition to the mesocorticolimbic dopaminergic circuitry,
a significant body of evidence has described the role of the habenulo-interpeduncular
circuit in mediating the withdrawal effects of nicotine (Velasquez et al., 2014). In
fact, during nicotine withdrawal, GABAergic neurons in the interpeduncular nucleus
are activated by glutamatergic afferents from the medial habenula (Zhao-Shea et al.,
2013). In summary, above-described studies suggest that the mesocorticolimbic do-
paminergic neurons and the habenulo-interpeduncular circuit play an important role
in mediating the unpleasant affective symptoms associated with nicotine withdrawal.
Exposure to environmental cues and contexts among abstinent smokers can result
in intense cravings and reactivation of nicotine-associated memories leading to re-
lapse. Thus, associative learning between nicotine and environmental cues plays an
important role in the process of relapse (Stoker and Markou, 2015). As described
above, the mesocorticolimbic dopaminergic neurons from the VTA project to a
number of cortical and limbic nuclei, such as the PFC, amygdala, hippocampus,
and NAcc, that are involved in the process of learning between environmental cues
and nicotine, as well as emotional responses to nicotine-associated stimuli. Empirical
evidence supports a role for several cortical structures including the insular cortex,
medial PFC, hippocampus in the process of drug craving, and relapse (Koob and
Volkow, 2010). In addition, subcortical structures such as the NAcc core and
VTA, which receive excitatory inputs from the cortical structures described above,
are implicated in the reinstatement of nicotine seeking (Gipson et al., 2013;
4 Neural substrates underlying nicotine dependence 201
Grieder et al., 2014). In summary, even though several distinct brain nuclei/regions
are involved in the different nicotine-dependent behaviors, it must be emphasized that
these brain regions closely regulate each other and often form parts of overlapping
circuitries. We will now describe the role of specific neurotransmitters and receptors
in the above-described brain regions in nicotine withdrawal and reinstatement of nic-
otine seeking.
4 NEURAL SUBSTRATES UNDERLYING NICOTINE

DEPENDENCE
4.1 CHOLINERGIC NEUROTRANSMISSION AND NICOTINE
DEPENDENCE
The action of endogenous acetylcholine in the brain is mediated by neuronal
nAChRs, which are widely distributed in the brain. Neuronal nAChRs are excitatory
ligand-gated ion channels composed of five subunits, which come together to form a
functional receptor (Dani and Bertrand, 2007). Most of the neuronal nAChRs are het-
eromeric and composed of different isoforms of alpha (a2–a9) and beta (b1–b4) sub-
units. Heteromeric nAChRs have a lot of diversity and can vary in their
pharmacological responses based on the particular combination of alpha and beta
receptor subunits and differences in stoichiometry of nAChRs (Changeux, 2010;
Zoli et al., 2015). For example, the pharmacological response of a neuronal nAChR
having two a4 subunits and three b2 subunits [(a4)2(b2)3] will be different from a
nAChR having three a4 subunits and two b2 subunits [(a4)3(b2)2]. In contrast, some
neuronal nAChRs are homomeric and consist of five a7 subunits. Importantly,
chronic exposure of nicotine induces neuroadaptations in expression of nAChRs
resulting in either upregulation or downregulation of the nAChRs in different parts
of the brain (Colombo et al., 2013). Finally, the neuronal nAChRs exist as hetero-
receptors on presynaptic terminals of a number of neurotransmitters including dopa-
mine, serotonin, glutamate, and GABA and can alter the release of these
neurotransmitters when activated by nicotine/acetylcholine (Balfour, 2009). NAChR
subunits also play an important role in the reinforcing effects of nicotine. However,
the discussion of nAChR subunits mediating the reinforcing effects of nicotine is be-
yond the scope of this review, and the reader is referred to other scholarly work for a
discussion on this topic (D’Souza and Markou, 2011; Li et al., 2014; Picciotto et al.,
1998). In this review, we will mainly discuss the role of the nAChR subunits in the
withdrawal effects of nicotine and reinstatement of nicotine seeking.
Several specific nAChR subunits mediate the unpleasant somatic and affective
effects associated with nicotine withdrawal in nicotine-dependent animals. For ex-
ample, knockout of either the b4, a2, a5, or a7 subunits attenuated the somatic signs
of nicotine withdrawal in nicotine-dependent mice compared to their respective
wild-type counterparts (Jackson et al., 2008; Salas et al., 2004, 2009). The nAChRs
also mediate the unpleasant affective symptoms associated with nicotine withdrawal.
Both systemic and intra-VTA administration of dihydrobetaerythroidine (DhbE), a

nAChR antagonist selective for the a4b2-containing nAChRs, elevated intracranial
self-stimulation (ICSS) thresholds in nicotine-dependent rats (Bruijnzeel and
Markou, 2004; Epping-Jordan et al., 1998; see Table 2). This DhbE-induced eleva-
tion of ICSS thresholds in nicotine-dependent rats suggests the development of nic-
otine withdrawal-induced anhedonia-like state in animals. Interestingly, mice
lacking either the b4 or a7 nAChR subunits showed delayed onset of nicotine
withdrawal-induced anhedonia-like state (Stoker et al., 2012a). In addition, pharma-
cological blockade of the a6 subunit-containing nAChRs attenuated the nicotine
withdrawal-induced anxiety and conditioned place aversion in mice, suggesting a
role for a6 subunit-containing nAChRs in the unpleasant affective effects of nicotine
withdrawal (Jackson et al., 2009). Overall, the data suggest that the unpleasant phys-
ical signs associated with nicotine withdrawal are mediated by the nAChRs that con-
tain either the b4, a2, a5, or a7 subunits. Furthermore, the data suggest that the
unpleasant affective signs associated with nicotine withdrawal are mediated by
the nAChRs that contain the b2, b4, a4, a6, or a7 subunits.
The nAChRs are also involved in the reinstatement of nicotine seeking in ani-
mals, a putative model for relapse in humans. Administration of methyllycaconitine,
a selective antagonist of the a7-containing nAChRs, attenuated cue-induced rein-
statement of nicotine seeking in rats (Liu, 2014). NAChRs containing the a7 subunits
are often found as heteroreceptors on presynaptic glutamate terminals, and activation
of these a7-containing nAChRs increases glutamate release. A recent study has
shown that blockade of glutamatergic transmission via N-methyl-D-aspartate
(NMDA) receptors attenuated cue-induced reinstatement of nicotine seeking
(Gipson et al., 2013). Therefore, the decrease in cue-induced reinstatement of nico-
tine seeking due to blockade of the a7-containing nAChRs could be due to blockade
of release of other neurotransmitters such as glutamate. Varenicline, a partial agonist
at the a4b2-containing nAChRs, attenuated nicotine-induced, but not cue-induced,
reinstatement of nicotine seeking in rats (O’Connor et al., 2010). Taken together, data
from the above-described studies suggest that nAChRs with different subunit com-
positions may have a differential role in reinstatement of nicotine seeking. For ex-
ample, a7-containing nAChRs possibly mediate cue-induced reinstatement of
nicotine seeking, while the a4b2-containing nAChRs possibly mediate the
nicotine-induced reinstatement of nicotine seeking. Future studies using optoge-
netics and molecular biology tools are needed to identify the role of the nAChRs
in specific neural circuits that are involved in the different types of reinstatement
models described above (cue- vs. nicotine-induced reinstatement of nicotine seek-
ing). In another study, galantamine, an acetylcholinesterase inhibitor and a nonselec-
tive positive modulator of nAChRs, attenuated cue-induced reinstatement of nicotine
seeking (Hopkins et al., 2012). In summary, targeting specific nAChR subunits may
help alleviate unpleasant effects of nicotine withdrawal and prevent relapse among
abstinent smokers. Thus, medications targeting specific nAChR subunits may gen-
erate smoking cessation medications with better efficacy compared to currently ap-
proved FDA medications.
4.2 GLUTAMATE NEUROTRANSMISSION AND NICOTINE DEPENDENCE

Glutamate is the major excitatory neurotransmitter in the mammalian brain, and its
action is mediated by fast-acting ionotropic and slow-acting G protein-coupled meta-
botropic receptors (Conn and Pin, 1997; Hollmann and Heinemann, 1994). The iono-
tropic receptors include NMDA, amino-3-hydroxy-5-methyl-4-isoxazolepropionate
(AMPA), and kainate receptors. The metabotropic glutamate (mGlu) receptors are
classified into Group I (mGlu1 and mGlu5), Group II (mGlu2 and mGlu3), and
Group III (mGlu4, mGlu6, mGlu7, and mGlu8) receptors depending on their signal
transduction pathways, sequence homology, and pharmacological selectivity (Pin
and Duvoisin, 1995). Nicotine increases glutamate release by binding to excitatory
a7-containing nAChRs located on presynaptic glutamatergic terminals (Mansvelder
and McGehee, 2002).
It is hypothesized that chronic nicotine exposure leads to the development of a
hypoglutamatergic state, which is responsible for the unpleasant affective state as-
sociated with nicotine withdrawal (Markou, 2008). Consistent with this hypothesis,
blockade of glutamatergic transmission using either the AMPA receptor antagonist
(NBQX) or the mGlu5 receptor antagonist (MPEP) resulted in the elevation of ICSS
thresholds in nicotine-dependent rats, suggesting development of an anhedonia-like
aversive state (Kenny et al., 2003; Liechti and Markou, 2007). Interestingly,
nicotine-dependent mice lacking the mGlu5 receptor showed attenuated
anhedonia-like aversive state during nicotine withdrawal compared to their wild-
type counterparts (Stoker et al., 2012b). The difference in findings with respect to
the mGlu5 receptors between the pharmacological and genetic studies described
above could be attributed to neuroadaptations that are often seen in congenital
knockout mice. Overall, the data suggest that blockade of glutamatergic transmission
worsens the unpleasant affective effects associated with nicotine withdrawal and
thus reversal of nicotine-induced hypoglutamatergic state may help alleviate the un-
pleasant effects of nicotine withdrawal.
Interestingly, increased glutamate levels have been reported following exposure
to nicotine-associated cues in the core subdivision of the NAcc (Gipson et al., 2013).
Blockade of the NMDA-mediated glutamatergic transmission after systemic admin-
istration of ifenprodil, a NMDA receptor antagonist, attenuated cue-induced rein-
statement of nicotine seeking (Gipson et al., 2013). The same study also showed
that injections of a NMDA receptor antagonist selective for the NR2A subunit
(TCN-201) in the NAcc core attenuated cue-induced reinstatement of nicotine seek-
ing. In contrast to these findings, blockade of the NMDA receptors in the NAcc core
by the competitive NMDA receptor antagonist LY235959 increased cue-induced re-
instatement of nicotine seeking compared to saline control (D’Souza and Markou,
2014). The differential effects observed between the above-described studies could
be either due to selectivity of the different compounds (LY235959 vs. TCN-201) for
the different NMDA receptor subunits and/or the differential localization (synaptic
vs. extrasynaptic) of the NMDA receptors containing these different subunits. More
work will be required to determine the precise role of the NMDA receptors in the
NAcc core in cue-induced reinstatement of nicotine seeking. Furthermore, cue-

induced reinstatement of nicotine seeking was attenuated following blockade of glu-
tamate transmission via manipulation of the mGlu5 and mGlu2/3 receptors
(Bespalov et al., 2005; Liechti et al., 2007). In addition to glutamate receptors,
the levels of synaptic glutamate are regulated by uptake transporter proteins such
as the cystine–glutamate antiporter (Nicholls and Attwell, 1990). N-acetylcysteine,
which binds to the cystine–glutamate antiporter and increases levels of extrasynaptic
glutamate levels, attenuated the cue-induced reinstatement of nicotine seeking
(Ramirez-Nino et al., 2013). These data support a role for the cystine–glutamate ex-
changer in the cue-induced reinstatement of nicotine seeking. It is hypothesized that
the increase in extrasynaptic glutamate transmission may help reverse the hypoglu-
tamatergic state induced by chronic nicotine exposure. In summary, several glutama-
tergic receptors described above can serve as targets for smoking cessation
medications. The mGlu receptors may be better targets for smoking cessation med-
ications compared to iGlu receptors, because the mGlu receptors subtly modulate
glutamate transmission, and it is hypothesized that manipulation of the mGlu recep-
tors will produce fewer side effects compared to the iGlu receptors (D’Souza and
Markou, 2012).
4.3 GABA NEUROTRANSMISSION AND NICOTINE DEPENDENCE

GABA is the major inhibitory neurotransmitter in the brain. The actions of endog-
enously released GABA are mediated by ionotropic (GABAA and GABAC) and
metabotropic (GABAB) receptors. Nicotine increases GABA neurotransmission
by binding to excitatory nAChRs located on presynaptic GABA neurons. Impor-
tantly, the nAChRs located on GABAergic neurons undergo rapid desensitization,
and chronic nicotine exposure is associated with decreased GABA transmission
(Mansvelder et al., 2002). Consistent with this hypothesis, systemic administration
of the GABAB agonist baclofen attenuated the somatic signs of nicotine with-
drawal in nicotine-dependent mice (Varani et al., 2014). In contrast, both the
GABAB receptor agonist (CGP44532) and the GABAB receptor positive allosteric
modulator (PAM) (BHF177) elevated ICSS thresholds during nicotine withdrawal
in animals, indicating an exacerbation of the anhedonia-like aversive effects asso-
ciated with nicotine withdrawal (Vlachou et al., 2011b). Together, these data sug-
gest that the GABAB receptors play a differential role in somatic versus affective
manifestations of nicotine withdrawal. The differences between the studies could
be attributed to methodological differences (measurement of affective vs. somatic
signs) and differences in species (rats vs. mice) used in the above studies. Inter-
estingly, the GABAB receptor antagonist (CGP56433) also exacerbated the
anhedonia-like effects of nicotine withdrawal (Vlachou et al., 2011b). The similar
effects of the GABAB receptor agonist/PAM and GABAB receptor antagonist on
the unpleasant affective effects associated with nicotine withdrawal could be due
to action of these compounds at the GABAB receptors located at differential sites
such as the presynaptic versus postsynaptic neurons. In addition, these effects
could also be explained by the differential action of these GABAB compounds
at different GABAB subunits such as the GABAB1 versus GABAB2. Further work
will be required to fully understand the role of the GABAB receptors in the affec-
tive and somatic effects associated with nicotine withdrawal. Finally, both the
GABAB receptor agonists (CGP44532) and the GABAB receptor PAM attenuated
cue-induced reinstatement of nicotine seeking (Paterson et al., 2005; Vlachou
et al., 2011a). Overall, the data suggest that the GABAB receptors can serve as
useful targets for smoking cessation medications.
4.4 ENDOGENOUS OPIOID SIGNALING AND NICOTINE DEPENDENCE

Endogenous opioids such as b-endorphin, met- and leu-enkephalin, and dynorphins
are also involved in the development of nicotine dependence (Berrendero et al.,
2010). The effects of b-endorphin, enkephalin, and dynorphin are mediated by three
different subtypes of opioid receptors, namely, the mu, delta, and kappa-opioid re-
ceptors, respectively (Lutz and Pfister, 1992). Nicotine increases endogenous opioid
neurotransmission by binding to nAChRs located on presynaptic terminals of neu-
rons containing opioid peptides (Hadjiconstantinou and Neff, 2011). Administration
of the nonselective opioid receptor antagonist naloxone, to nicotine-dependent rats
and mice, precipitated the somatic signs associated with nicotine withdrawal (Biala
et al., 2005; Malin et al., 1993). Naloxone also precipitated nicotine withdrawal in a
small group of nicotine-dependent smokers (Krishnan-Sarin et al., 1999). It is hy-
pothesized that this naloxone-precipitated nicotine withdrawal syndrome could be
mediated by binding of naloxone to nAChRs. In contrast, nicotine-dependent mice
lacking the mu-opioid receptors or preproenkephalin gene showed attenuated so-
matic signs of nicotine withdrawal as compared to their respective wild-type controls
(Berrendero et al., 2002, 2005). The discrepancy between these genetic and pharma-
cological studies described above could be due to compensatory changes in mice
lacking a specific protein during development. In contrast to the mu and delta opioid
receptors, blockade of the kappa opioid receptors using norbinaltorphimine (nor-
BNI) attenuated the unpleasant somatic and affective nicotine withdrawal signs in
nicotine-dependent animals (Jackson et al., 2010; Tejeda et al., 2012; but also see
Ise et al., 2002). Blockade of the kappa opioid receptors using nor-BNI attenuated
stress-induced, but not cue-induced, reinstatement of nicotine seeking (Grella
et al., 2014). In addition, naltrexone attenuated cue-induced reinstatement of nicotine
seeking in rats (Liu et al., 2009). Overall, opioid receptors may be useful targets for
alleviation of nicotine withdrawal symptoms and prevention of relapse among absti-
nent smokers.
4.5 ENDOCANNABINOID SIGNALING AND NICOTINE DEPENDENCE

The effects of endogenous cannabinoids anandamide and 2 arachidonylglycerol are
mediated by the CB1 and CB2 cannabinoid receptors. Furthermore, the levels of en-
dogenous cannabinoids can be increased by inhibiting their degradative enzymes
such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase. Adminis-
tration of delta-9-tetrahydrocannabinol (THC), the primary active constituent of
marijuana, attenuated the somatic and affective signs associated with nicotine with-
drawal in rats (Balerio et al., 2004). Consistent with these studies, the FAAH inhib-
itor (URB597), which increases endogenous cannabinoid signaling, reduced nicotine
withdrawal-induced anxiety in rats (Cippitelli et al., 2011). However, knockout of
either the CB1 or CB2 receptors did not worsen expression of somatic nicotine with-
drawal signs as compared to their respective wild-type counterparts (Castane et al.,
2002; Ignatowska-Jankowska et al., 2013).
Blockade of the CB1 receptors attenuated both cue- and nicotine-induced rein-
statement of nicotine seeking (Diergaarde et al., 2008; Forget et al., 2009). In con-
trast, reinstatement of nicotine seeking was also attenuated by increasing
endocannabinoid signaling via blockade of the anandamide transporter with
AM404 (Gamaleddin et al., 2013). It is not clear why the blockade of the CB1 recep-
tors and increase in anandamide levels had similar effects on reinstatement of nic-
otine seeking. It is hypothesized that CB1 receptor antagonists may act in
neurocircuits that express endocannabinoid ligands other than anandamide. In sum-
mary, the above data support a role for endocannabinoid signaling in nicotine depen-
dence, and the CB1 receptors and anandamide transporter can serve as possible
targets for future smoking cessation medications.
4.6 ROLE OF OTHER NEUROBIOLOGICAL SUBSTRATES IN NICOTINE

DEPENDENCE
The role of monoamines such as dopamine, noradrenaline, and serotonin in nico-
tine dependence is discussed in Table 3. Several studies have reported a role for
other peptides such as melanocortin, orexin/hypocretin, galanin, CRF, neurokinins,
brain-derived neurotrophic factor, and alpha-peroxisome proliferator receptors in
nicotine withdrawal and nicotine seeking (Dao et al., 2014; Jackson et al., 2011;
Kivinummi et al., 2011; Plaza-Zabala et al., 2012, 2013). In addition, several sig-
naling molecules such as calcium/calmodulin-dependent protein kinases II and IV
and cyclic-AMP response element-binding protein are involved in nicotine-
dependent behaviors (Jackson and Damaj, 2009; Kivinummi et al., 2011). The dis-
cussion of these neuromediators/neuropeptides and signaling molecules is beyond
the scope of this review, and the reader is referred to other scholarly reviews
for a discussion on the above-described molecules (Barik and Wonnacott, 2009;
Brunzell and Picciotto, 2009; Jackson et al., 2014; Kenny, 2011; Picciotto and
Mineur, 2014).
Table 3 Role of Monoamines (Dopamine, Noradrenaline, and Serotonin) in Nicotine-Dependent Behaviors
Nicotine-
Dependent
Neurotransmitters Behavior Treatment Effects on Behavior References
Dopamine Nicotine Weak inhibitor of dopamine Decreased nicotine withdrawal-induced Paterson

withdrawal transporter (Bupropion) somatic signs et al. (2007)
Weak inhibitor of dopamine Reversed nicotine withdrawal-induced Paterson
transporter (Bupropion) elevation in ICSS thresholds et al. (2007)
Reinstatement of D1 antagonist (SCH23390) Decreased cue-induced reinstatement Liu et al.
nicotine seeking of nicotine seeking (2010)
D2 antagonist (Eticlopride) Decreased cue-induced reinstatement Liu et al.
of nicotine seeking (2010)
D3 antagonist (SB277011-A) Decreased cue- and nicotine-induced Khaled et al.
reinstatement of nicotine seeking (2010)
D4 antagonist (L-745870) Decreased cue- and nicotine-induced Yan et al.
reinstatement of nicotine seeking (2012)
Serotonin Nicotine 5-Hydroxytryptophan (serotonin Decreased nicotine withdrawal-induced Ohmura
withdrawal precursor) somatic signs et al. (2011)
Selective serotonin reuptake Reversed nicotine withdrawal-induced Harrison
inhibitor (SSRI) + 5HT1A antagonist elevation in ICSS thresholds et al. (2001)
5HT3 antagonist (Ondansetron) Attenuated nicotine withdrawal-induced Suzuki et al.
CPA (1997)
Reinstatement of 5HT2A receptor antagonist Decreased cue- and nicotine-induced Fletcher et al.
nicotine seeking (M100907) reinstatement of nicotine seeking (2012)
5HT2c receptor agonist (Ro60- Decreased cue- and nicotine-induced Fletcher et al.
0175) reinstatement of nicotine seeking (2012)
Noradrenaline Reinstatement of a1 Receptor antagonist (Prazosin) Decreased cue- and nicotine-induced Forget et al.
nicotine seeking reinstatement of nicotine seeking (2010)
b Blocker (Propranolol) Decreased cue-induced reinstatement Chiamulera
of nicotine seeking et al. (2010)
ICSS, intracranial self-stimulation; CPA, conditioned place aversion.


Nicotine is a highly addictive substance, and tobacco smoking is a major burden on
healthcare systems all over the world. In this review, several brain regions that play a
role in the development of nicotine dependence have been described. Furthermore,
this review has described both nicotinic and nonnicotinic neural substrates that play
a role in nicotine withdrawal and nicotine seeking. Currently, available FDA-
approved smoking cessation medications target neuronal nAChRs, which will con-
tinue to remain an important target for future smoking cessation medications. This
review has described the role of specific subunits of nAChRs that play an important
role in both nicotine withdrawal and seeking. Targeting these specific nAChR sub-
units may result in more efficacious smoking cessation medications compared to those
currently available. However, the wide distribution of nAChRs, existence of nAChRs
as heteroreceptors and autoreceptors, neuroadaptations in the functioning of nAChRs
(upregulation vs. downregulation) upon chronic nicotine exposure, and the difference
in pharmacological response of nAChRs to both nicotine and acetylcholine due to
nAChR stoichiometry, makes targeting nAChRs for the treatment of nicotine depen-
dence extremely challenging. Thus, in addition to nAChRs, it is imperative to look at
nonnicotinic neural substrates that play a role in the development of nicotine depen-
dence. Studies using animal models suggest an important role for other neurotrans-
mitters like dopamine, glutamate, GABA, serotonin, noradrenaline, and signaling
peptides such as opioids and endocannabinoids in the development of nicotine depen-
dence. It remains to be seen whether the promise of several neural targets obtained
from animal studies will result in the availability of clinically efficacious smoking
cessation medications. In summary, the challenge of reducing the burden of tobacco
smoking in society will require the discovery of new smoking cessation medications
and will involve targeting both nicotinic and nonnicotinic neural substrates.
ACKNOWLEDGMENTS
This work was supported by Bower, Bennet, and Bennet Endowed Chair Research Award
awarded to Dr. Manoranjan S. D’Souza by The Raabe College of Pharmacy, Ohio Northern
University (ONU), Ada, Ohio. The author would also like to thank Mr. Haval Norman
(Pharmacy candidate 2018, The Raabe College of Pharmacy, Ohio Northern University,
ONU) for editorial comments on the manuscript.
Disclosures: Manoranjan D’Souza reports no financial conflicts of interests.
REFERENCES
Balerio, G.N., et al., 2004. Delta9-tetrahydrocannabinol decreases somatic and motivational
manifestations of nicotine withdrawal in mice. Eur. J. Neurosci. 20, 2737–2748.
Balfour, D.J., 2009. The neuronal pathways mediating the behavioral and addictive properties
of nicotine. Handb. Exp. Pharmacol. 192, 209–233.
References 209
Barik, J., Wonnacott, S., 2009. Molecular and cellular mechanisms of action of nicotine in the
CNS. Handb. Exp. Pharmacol. 192, 173–207.
Berrendero, F., Kieffer, B.L., Maldonado, R., 2002. Attenuation of nicotine-induced antino-
ciception, rewarding effects, and dependence in mu-opioid receptor knock-out mice.
J. Neurosci. 22, 10935–10940.
Berrendero, F., et al., 2005. Nicotine-induced antinociception, rewarding effects, and physical
dependence are decreased in mice lacking the preproenkephalin gene. J. Neurosci.
25, 1103–1112.
Berrendero, F., et al., 2010. Neurobiological mechanisms involved in nicotine dependence and
reward: participation of the endogenous opioid system. Neurosci. Biobehav. Rev.
35, 220–231.
Bespalov, A.Y., et al., 2005. Metabotropic glutamate receptor (mGluR5) antagonist MPEP
attenuated cue- and schedule-induced reinstatement of nicotine self-administration behav-
ior in rats. Neuropharmacology 49 (Suppl. 1), 167–178.
Biala, G., Budzynska, B., Kruk, M., 2005. Naloxone precipitates nicotine abstinence
syndrome and attenuates nicotine-induced antinociception in mice. Pharmacol. Rep.
57, 755–760.
Bruijnzeel, A.W., Markou, A., 2004. Adaptations in cholinergic transmission in the ventral
tegmental area associated with the affective signs of nicotine withdrawal in rats.
Brunzell, D.H., Picciotto, M.R., 2009. Molecular mechanisms underlying the motivational
effects of nicotine. Nebr. Symp. Motiv. 55, 17–30.
Carmody, T.P., 1992. Preventing relapse in the treatment of nicotine addiction: current issues
and future directions. J. Psychoactive Drugs 24, 131–158.
Castane, A., et al., 2002. Lack of CB1 cannabinoid receptors modifies nicotine behavioural
responses, but not nicotine abstinence. Neuropharmacology 43, 857–867.
Changeux, J.P., 2010. Allosteric receptors: from electric organ to cognition. Annu. Rev. Phar-
macol. Toxicol. 50, 1–38.
Chiamulera, C., et al., 2010. Propranolol transiently inhibits reinstatement of nicotine-seeking
behaviour in rats. J. Psychopharmacol. 24, 389–395.
Cippitelli, A., et al., 2011. Endocannabinoid regulation of acute and protracted nicotine with-
drawal: effect of FAAH inhibition. PLoS One 6, e28142.
Colombo, S.F., et al., 2013. Biogenesis, trafficking and up-regulation of nicotinic ACh recep-
tors. Biochem. Pharmacol. 86, 1063–1073.
Conn, P.J., Pin, J.P., 1997. Pharmacology and functions of metabotropic glutamate receptors.
Annu. Rev. Pharmacol. Toxicol. 37, 205–237.
Dani, J.A., Bertrand, D., 2007. Nicotinic acetylcholine receptors and nicotinic cholinergic
mechanisms of the central nervous system. Annu. Rev. Pharmacol. Toxicol. 47, 699–729.
Dao, D.Q., et al., 2014. Nicotine enhances excitability of medial habenular neurons via facil-
itation of neurokinin signaling. J. Neurosci. 34, 4273–4284.
De Biasi, M., Dani, J.A., 2011. Reward, addiction, withdrawal to nicotine. Annu. Rev. Neu-
rosci. 34, 105–130.
Diergaarde, L., et al., 2008. Contextual renewal of nicotine seeking in rats and its suppression
by the cannabinoid-1 receptor antagonist Rimonabant (SR141716A). Neuropharmacology
55, 712–716.
D’Souza, M.S., Markou, A., 2011. Neuronal mechanisms underlying development of nicotine
dependence: implications for novel smoking-cessation treatments. Addict. Sci. Clin. Pract.
6, 4–16.
D’Souza, M.S., Markou, A., 2012. The “Stop” & “Go” of nicotine dependence: role of GABA
and glutamate. In: Pierce, R.C., Kenny, P.J., (Eds.), Addiction: A Neurobiological Per-
spective. Cold Spring Harbor Press, New York, pp. 251–268.
D’Souza, M.S., Markou, A., 2014. Differential role of N-methyl-D-aspartate receptor-
mediated glutamate transmission in the nucleus accumbens shell and core in nicotine seek-
ing in rats. Eur. J. Neurosci. 39, 1314–1322.
Epping-Jordan, M.P., et al., 1998. Dramatic decreases in brain reward function during nicotine
withdrawal. Nature 393, 76–79.
Fagerstrom, K., 2002. The epidemiology of smoking: health consequences and benefits of ces-
sation. Drugs 62 (Suppl. 2), 1–9.
Fletcher, P.J., Rizos, Z., Noble, K., Soko, A.D., Silenieks, L.B., Le, A.D., Higgins, G.A., 2012.
Effects of the 5-HT2C receptor agonist Ro60-0175 and the 5-HT2A receptor antagonist
M100907 on nicotine self-administration and reinstatement. Neuropharmacology 62,
2288–2298.
Forget, B., Coen, K.M., Le Foll, B., 2009. Inhibition of fatty acid amide hydrolase
reduces reinstatement of nicotine seeking but not break point for nicotine self-
administration—comparison with CB(1) receptor blockade. Psychopharmacology
(Berl.) 205, 613–624.
Forget, B., et al., 2010. Noradrenergic alpha1 receptors as a novel target for the treatment of
nicotine addiction. Neuropsychopharmacology 35, 1751–1760.
Gamaleddin, I., et al., 2013. AM404 attenuates reinstatement of nicotine seeking induced by
nicotine-associated cues and nicotine priming but does not affect nicotine- and food-
taking. J. Psychopharmacol. 27, 564–571.
Geisler, S., Zahm, D.S., 2005. Afferents of the ventral tegmental area in the rat-anatomical
substratum for integrative functions. J. Comp. Neurol. 490, 270–294.
Gipson, C.D., et al., 2013. Reinstatement of nicotine seeking is mediated by glutamatergic
plasticity. Proc. Natl. Acad. Sci. U.S.A. 110, 9124–9129.
Grace, A.A., et al., 2007. Regulation of firing of dopaminergic neurons and control of goal-
directed behaviors. Trends Neurosci. 30, 220–227.
Grella, S.L., et al., 2014. Role of the kappa-opioid receptor system in stress-induced reinstate-
ment of nicotine seeking in rats. Behav. Brain Res. 265, 188–197.
Grieder, T.E., et al., 2014. VTA CRF neurons mediate the aversive effects of nicotine with-
drawal and promote intake escalation. Nat. Neurosci. 17, 1751–1758.
Hadjiconstantinou, M., Neff, N.H., 2011. Nicotine and endogenous opioids: neurochemical
and pharmacological evidence. Neuropharmacology 60, 1209–1220.
Hadjiconstantinou, M., et al., 2011. Enhanced dopamine transporter function in striatum dur-
ing nicotine withdrawal. Synapse 65, 91–98.
Harrison, A.A., Liem, Y.T., Markou, A., 2001. Fluoxetine combined with a serotonin-1A
receptor antagonist reversed reward deficits observed during nicotine and amphetamine
withdrawal in rats. Neuropsychopharmacology 25, 55–71.
Henningfield, J.E., Miyasato, K., Jasinski, D.R., 1985. Abuse liability and pharmacodynamic
characteristics of intravenous and inhaled nicotine. J. Pharmacol. Exp. Ther. 234, 1–12.
Hildebrand, B.E., et al., 1998. Reduced dopamine output in the nucleus accumbens but not in
the medial prefrontal cortex in rats displaying a mecamylamine-precipitated nicotine with-
drawal syndrome. Brain Res. 779, 214–225.
Hollmann, M., Heinemann, S., 1994. Cloned glutamate receptors. Annu. Rev. Neurosci.
17, 31–108.
References 211
Hopkins, T.J., et al., 2012. Galantamine, an acetylcholinesterase inhibitor and positive alloste-
ric modulator of nicotinic acetylcholine receptors, attenuates nicotine taking and seeking
in rats. Neuropsychopharmacology 37, 2310–2321.
Hughes, J.R., et al., 1991. Symptoms of tobacco withdrawal. A replication and extension.
Arch. Gen. Psychiatry 48, 52–59.
Hughes, J.R., Keely, J., Naud, S., 2004. Shape of the relapse curve and long-term abstinence
among untreated smokers. Addiction 99, 29–38.
Ignatowska-Jankowska, B.M., et al., 2013. The cannabinoid CB2 receptor is necessary for
nicotine-conditioned place preference, but not other behavioral effects of nicotine in mice.
Psychopharmacology (Berl.) 229, 591–601.
Ise, Y., et al., 2002. Modulation of kappa-opioidergic systems on mecamylamine-precipitated
nicotine-withdrawal aversion in rats. Neurosci. Lett. 323, 164–166.
Jackson, K.J., Damaj, M.I., 2009. L-type calcium channels and calcium/calmodulin-dependent
kinase II differentially mediate behaviors associated with nicotine withdrawal in mice.
J. Pharmacol. Exp. Ther. 330, 152–161.
Jackson, K.J., et al., 2008. Differential role of nicotinic acetylcholine receptor subunits
in physical and affective nicotine withdrawal signs. J. Pharmacol. Exp. Ther. 325,
302–312.
Jackson, K.J., et al., 2009. The role of alpha6-containing nicotinic acetylcholine receptors in
nicotine reward and withdrawal. J. Pharmacol. Exp. Ther. 331, 547–554.
Jackson, K.J., et al., 2010. Effect of the selective kappa-opioid receptor antagonist JDTic on
nicotine antinociception, reward, and withdrawal in the mouse. Psychopharmacology
(Berl.) 210, 285–294.
Jackson, K.J., et al., 2011. The neuropeptide galanin and variants in the GalR1 gene are
associated with nicotine dependence. Neuropsychopharmacology 36, 2339–2348.
Jackson, K.J., et al., 2013. The a3b4* nicotinic acetylcholine receptor subtype mediates
nicotine reward and physical nicotine withdrawal signs independently of the a5 subunit
in the mouse. Neuropharmacology 70, 228–235.
Jackson, K.J., et al., 2014. New mechanisms and perspectives in nicotine withdrawal.
Jhou, T.C., et al., 2009. The mesopontine rostromedial tegmental nucleus: a structure targeted
by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia
nigra compacta. J. Comp. Neurol. 513, 566–596.
Kenny, P.J., 2011. Tobacco dependence, the insular cortex and the hypocretin connection.
Pharmacol. Biochem. Behav. 97, 700–707.
Kenny, P.J., Gasparini, F., Markou, A., 2003. Group II metabotropic and alpha-amino-
3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate glutamate receptors regu-
late the deficit in brain reward function associated with nicotine withdrawal in rats.
Khaled, M.A., et al., 2010. The selective dopamine D3 receptor antagonist SB 277011-A, but
not the partial agonist BP 897, blocks cue-induced reinstatement of nicotine-seeking. Int. J.
Neuropsychopharmacol. 13, 181–190.
Kivinummi, T., et al., 2011. Alterations in BDNF and phospho-CREB levels following chronic
oral nicotine treatment and its withdrawal in dopaminergic brain areas of mice. Neurosci.
Lett. 491, 108–112.
Koob, G.F., Volkow, N.D., 2010. Neurocircuitry of addiction. Neuropsychopharmacology
35, 217–238.
Krishnan-Sarin, S., Rosen, M.I., O’Malley, S.S., 1999. Naloxone challenge in smokers. Pre-
liminary evidence of an opioid component in nicotine dependence. Arch. Gen. Psychiatry
56, 663–668.
Li, X., et al., 2014. Involvement of glutamatergic and GABAergic systems in nicotine
dependence: implications for novel pharmacotherapies for smoking cessation.
Neuropharmacology 76 (Pt. B), 554–565.
Liechti, M.E., Markou, A., 2007. Interactive effects of the mGlu5 receptor antagonist
MPEP and the mGlu2/3 receptor antagonist LY341495 on nicotine self-administration
and reward deficits associated with nicotine withdrawal in rats. Eur. J. Pharmacol.
554, 164–174.
Liechti, M.E., et al., 2007. Metabotropic glutamate 2/3 receptors in the ventral tegmental area
and the nucleus accumbens shell are involved in behaviors relating to nicotine dependence.
J. Neurosci. 27, 9077–9085.
Liu, X., 2014. Effects of blockade of alpha4beta2 and alpha7 nicotinic acetylcholine receptors
on cue-induced reinstatement of nicotine-seeking behaviour in rats. Int. J. Neuropsycho-
pharmacol. 17, 105–116.
Liu, X., et al., 2009. Naltrexone attenuation of conditioned but not primary reinforcement of
nicotine in rats. Psychopharmacology (Berl.) 202, 589–598.
Liu, X., et al., 2010. Effects of dopamine antagonists on drug cue-induced reinstatement of
nicotine-seeking behavior in rats. Behav. Pharmacol. 21, 153–160.
Lutz, R.A., Pfister, H.P., 1992. Opioid receptors and their pharmacological profiles. J. Recept.
Res. 12, 267–286.
Malin, D.H., et al., 1993. Naloxone precipitates nicotine abstinence syndrome in the rat. Psy-
chopharmacology (Berl.) 112, 339–342.
Mansvelder, H.D., McGehee, D.S., 2002. Cellular and synaptic mechanisms of nicotine addic-
tion. J. Neurobiol. 53, 606–617.
Mansvelder, H.D., Keath, J.R., McGehee, D.S., 2002. Synaptic mechanisms underlie nicotine-
induced excitability of brain reward areas. Neuron 33, 905–919.
Markou, A., 2008. Review. Neurobiology of nicotine dependence. Philos. Trans. R. Soc. Lond.
B Biol. Sci. 363, 3159–3168.
Natividad, L.A., et al., 2009. Nicotine withdrawal produces a decrease in extracellular levels of
dopamine in the nucleus accumbens that is lower in adolescent versus adult male rats.
Synapse 64, 136–145.
Nicholls, D., Attwell, D., 1990. The release and uptake of excitatory amino acids. Trends Phar-
macol. Sci. 11, 462–468.
Nides, M., 2008. Update on pharmacologic options for smoking cessation treatment. Am. J.
Med. 121, S20–S31.
O’Connor, E.C., et al., 2010. The alpha4beta2 nicotinic acetylcholine-receptor partial
agonist varenicline inhibits both nicotine self-administration following repeated
dosing and reinstatement of nicotine seeking in rats. Psychopharmacology (Berl.)
208, 365–376.
Ohmura, Y., et al., 2011. 5-Hydroxytryptophan attenuates somatic signs of nicotine with-
drawal. J. Pharmacol. Sci. 117, 121–124.
Paterson, N.E., Balfour, D.J., Markou, A., 2007. Chronic bupropion attenuated the anhedonic
component of nicotine withdrawal in rats via inhibition of dopamine reuptake in the nu-
cleus accumbens shell. Eur J Neurosci. 25, 3099–3108.
References 213
Paterson, N.E., Froestl, W., Markou, A., 2005. Repeated administration of the GABAB recep-
tor agonist CGP44532 decreased nicotine self-administration, and acute administration de-
creased cue-induced reinstatement of nicotine-seeking in rats. Neuropsychopharmacology
30, 119–128.
Picciotto, M.R., Mineur, Y.S., 2014. Molecules and circuits involved in nicotine addiction: the
many faces of smoking. Neuropharmacology 76 (Pt. B), 545–553.
Picciotto, M.R., et al., 1998. Acetylcholine receptors containing the beta2 subunit are involved
in the reinforcing properties of nicotine. Nature 391, 173–177.
Pin, J.P., Duvoisin, R., 1995. The metabotropic glutamate receptors: structure and functions.
Plaza-Zabala, A., et al., 2012. Hypocretin/orexin signaling in the hypothalamic paraventricular
nucleus is essential for the expression of nicotine withdrawal. Biol. Psychiatry
71, 214–223.
Plaza-Zabala, A., et al., 2013. A role for hypocretin/orexin receptor-1 in cue-induced reinstate-
ment of nicotine-seeking behavior. Neuropsychopharmacology 38, 1724–1736.
Qi, X., et al., 2015. A critical role for the melanocortin 4 receptor in stress-induced relapse to
nicotine seeking in rats. Addict. Biol. 20, 324–335.
Ramirez-Nino, A.M., D’Souza, M.S., Markou, A., 2013. N-acetylcysteine decreased nicotine
self-administration and cue-induced reinstatement of nicotine seeking in rats: comparison
with the effects of N-acetylcysteine on food responding and food seeking. Psychopharma-
cology (Berl.) 225, 473–482.
Rennard, S.I., Daughton, D.M., 2014. Smoking cessation. Clin. Chest Med. 35, 165–176.
Salas, R., Pieri, F., De Biasi, M., 2004. Decreased signs of nicotine withdrawal in mice null for
the beta4 nicotinic acetylcholine receptor subunit. J. Neurosci. 24, 10035–10039.
Salas, R., et al., 2009. Nicotinic receptors in the habenulo-interpeduncular system are neces-
sary for nicotine withdrawal in mice. J. Neurosci. 29, 3014–3018.
Shaham, Y., et al., 2003. The reinstatement model of drug relapse: history, methodology and
major findings. Psychopharmacology (Berl.) 168, 3–20.
Shiffman, S.M., Jarvik, M.E., 1976. Smoking withdrawal symptoms in two weeks of absti-
nence. Psychopharmacology (Berl.) 50, 35–39.
Shram, M.J., et al., 2008. Interactions between age and the aversive effects of nicotine with-
drawal under mecamylamine-precipitated and spontaneous conditions in male Wistar rats.
Psychopharmacology (Berl.) 198, 181–190.
Stoker, A.K., Markou, A., 2015. Neurobiological bases of cue- and nicotine-induced reinstate-
ment of nicotine seeking: implications for the development of smoking cessation medica-
tions. Curr. Top. Behav. Neurosci. 24, 125–154.
Stoker, A.K., Olivier, B., Markou, A., 2012a. Role of alpha7- and beta4-containing nicotinic
acetylcholine receptors in the affective and somatic aspects of nicotine withdrawal: studies
in knockout mice. Behav. Genet. 42, 423–436.
Stoker, A.K., Olivier, B., Markou, A., 2012b. Involvement of metabotropic glutamate receptor
5 in brain reward deficits associated with cocaine and nicotine withdrawal and somatic
signs of nicotine withdrawal. Psychopharmacology (Berl.) 221, 317–327.
Stolerman, I.P., Jarvis, M.J., 1995. The scientific case that nicotine is addictive. Psychophar-
macology (Berl.) 117, 2–10. discussion 14–20.
Suzuki, T., et al., 1997. Attenuation of mecamylamine-precipitated nicotine-withdrawal aver-
sion by the 5-HT3 receptor antagonist ondansetron. Life Sci. 61, PL249–254.
Tejeda, H.A., et al., 2012. Dysregulation of kappa-opioid receptor systems by chronic nicotine
modulate the nicotine withdrawal syndrome in an age-dependent manner. Psychopharma-
cology (Berl.) 224, 289–301.
Varani, A.P., et al., 2014. Attenuation by baclofen of nicotine rewarding properties and nic-
otine withdrawal manifestations. Psychopharmacology (Berl.) 231, 3031–3040.
Velasquez, K.M., Molfese, D.L., Salas, R., 2014. The role of the habenula in drug addiction.
Front. Hum. Neurosci. 8, 174.
Vlachou, S., et al., 2011a. Repeated administration of the GABAB receptor positive modulator
BHF177 decreased nicotine self-administration, and acute administration decreased cue-
induced reinstatement of nicotine seeking in rats. Psychopharmacology (Berl.)
215, 117–128.
Vlachou, S., et al., 2011b. Both GABA(B) receptor activation and blockade exacerbated an-
hedonic aspects of nicotine withdrawal in rats. Eur. J. Pharmacol. 655, 52–58.
Watabe-Uchida, M., et al., 2012. Whole-brain mapping of direct inputs to midbrain dopamine
neurons. Neuron 74, 858–873.
WHO, 2011. WHO Report on the Global Tobacco Epidemic, 2011: Warning About the Dangers
of Tobacco. WHO website [online], http://www.who.int/tobacco/global_report/2011/en
(2011).
Yan, Y., et al., 2012. Blockade of dopamine d4 receptors attenuates reinstatement of extin-
guished nicotine-seeking behavior in rats. Neuropsychopharmacology 37, 685–696.
Zhao-Shea, R., et al., 2013. Activation of GABAergic neurons in the interpeduncular nucleus
triggers physical nicotine withdrawal symptoms. Curr. Biol. 23, 2327–2335.
Zoli, M., Pistillo, F., Gotti, C., 2015. Diversity of native nicotinic receptor subtypes in mam-
malian brain. Neuropharmacology 96 (Pt. B), 302–311.
CHAPTER
Neuroscience of alcohol
Neurobiological targets for
prevention and intervention
11
in adolescents
Anita Cservenka*, Bonnie J. Nagel*,†,1
*Departments of Psychiatry, Oregon Health & Science University, Portland, OR, USA
†
Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA
1
Abstract
Structural and functional neuroimaging studies indicate that heavy alcohol use during
adolescence may be neurotoxic to the brain. This chapter reviews the neuroimaging findings
in cross-sectional and longitudinal studies of adolescent heavy alcohol users. These youth
exhibit reductions in prefrontal, hippocampal, and cerebellar brain volume, decreased fronto-
parietal, and increased frontolimbic white matter integrity, as well as alterations in blood
oxygen level-dependent response during working memory, inhibitory control, verbal encoding,
decision making, and reward processing—some of which appear to differ between males and
females. Although some exist, additional longitudinal studies will significantly advance addic-
tion medicine by aiding prevention scientists and treatment providers to develop neurobiolo-
gically informed ways of strengthening neural networks prior to and after the onset of heavy
alcohol use, thereby promoting healthy cognitive functioning across the adolescent period.
Keywords
Alcohol, Adolescence, Brain volume, White matter, fMRI
1 INTRODUCTION
Human neuroscience research examining the impact of alcohol use on the brain has
made tremendous progress over the last 20 years. Advances in neuroimaging tech-
nology have allowed researchers to more carefully examine the effects of alcohol use
215
216 CHAPTER 11 Neuroscience of alcohol for addiction medicine
on brain structure and brain functioning. This work has provided a better understand-
ing of the brain systems most susceptible to the neurotoxic effects of alcohol and
could ultimately be used to neurobiologically inform treatment and rehabilitation ef-
forts. Prevention scientists may also benefit from this research, as neuroimaging
studies may foster translational efforts focused on behavioral or cognitive interven-
tions that strengthen brain networks shown to be vulnerable to the effects of alcohol.
An important population of study in the field of neuroimaging and alcohol use is
adolescents. The significance and advantages of studying youth to inform addiction
medicine are multifold. First, adolescence is a time of protracted brain maturation
(Giedd et al., 1999; Gogtay et al., 2004), during which affective and reward-related
neurocircuitry, including the mesolimbic system, is believed to mature prior to top-
down regulatory brain regions, such as the prefrontal cortex (PFC; Mills et al., 2014;
Van Leijenhorst et al., 2010). The ongoing maturation of the adolescent brain renders
it particularly vulnerable to neurotoxic substances, such as alcohol. Second, adoles-
cence is a time of alcohol use initiation, with alcohol being the most widely used in-
toxicating substance among youth. According to the 2014 Monitoring the Future
Survey (Johnston et al., 2015), while rates of adolescent alcohol are at their lowest
since initiation of the survey, alcohol use still increases substantially between the
8th and 12th grades, such that over a quarter of youth have consumed alcohol by
8th grade, and two-thirds of youth have consumed alcohol by the end of high school,
with 50% reporting being drunk by this time. Even more concerning, 20% of
12th graders reported binge drinking (consuming five or more drinks in one setting)
in the 2-week period prior to the survey. Many risk factors for increased alcohol use
have been reported during adolescence, including age at first drink (Dawson et al.,
2008), elevations in sensation seeking (Macpherson et al., 2010), cumulative life
stress (Casement et al., 2015), family history of alcoholism (FHP; Lieb et al.,
2002), and externalizing and internalizing symptoms (King et al., 2004). Thus,
ongoing brain maturation, incidence of binge drinking, and risk factors for alcohol
abuse during adolescence are all important motives to study the consequences of
alcohol’s effects on brain structure and functioning during this developmental
period. In this chapter, we outline the major findings that have been reported through
neuroimaging studies of alcohol use during adolescence and summarize areas
of research that can inform addiction medicine. We also emphasize the need for
additional efforts for the study of sex differences in the consequences and risk factors
for alcohol abuse during adolescence, as well as longitudinal studies of within-subject
change in brain structure, functioning, and neurocognition in alcohol-using youth.
2 BRAIN VOLUME
2.1 HIPPOCAMPUS
The hippocampus is a brain region critical for encoding new memories and has been
shown to be vulnerable to the effects of alcohol in animal models (Broadwater et al.,
2014) and adults with alcohol use disorders (AUDs; Beresford et al., 2006), which
2 Brain volume 217
makes it an important brain area of inquiry for research on alcohol’s neurotoxic ef-
fects during adolescence. Three studies of adolescents with AUDs have examined
hippocampal morphology (De Bellis et al., 2000; Medina et al., 2007; Nagel
et al., 2005). The first of these studies found that adolescents with AUDs had reduced
bilateral hippocampal volume compared with healthy controls, with longer duration
of alcohol use and earlier age of AUD onset related to smaller hippocampal volumes
(De Bellis et al., 2000). However, these findings were in a sample of AUD youth who
had comorbid psychiatric diagnoses, which could have confounded results, given
demonstrated hippocampal abnormalities in adolescents with psychopathology
alone, such as depression (Hulvershorn et al., 2011). A study thereafter in AUD
youth without comorbid psychiatric diagnoses also found reductions in hippocampal
volume, limited to the left hemisphere, and relative to controls (Nagel et al., 2005).
Interestingly, no “dose–response” relationship was found in this study, suggesting
only an association between the diagnosis of AUD and the hippocampal volume.
It is also possible that premorbid differences in hippocampal volume may have been
present between groups, prior to heavy alcohol consumption, suggesting reduced
hippocampal volume as a risk factor for AUDs in these adolescents. Finally, a sub-
sequent study replicated the findings of reduced left hippocampal volume in adoles-
cent alcohol users relative to controls or youth who used alcohol and marijuana
(Medina et al., 2007). This study also reported that increased right to left asymmetry
of the hippocampus in adolescent alcohol users was associated with the severity of
their alcohol abuse or dependence. Interestingly, while left to right asymmetry of the
hippocampus was related to verbal learning performance in controls, this relation-
ship was absent in alcohol users, suggesting a direct neurocognitive correlate of hip-
pocampal morphometry that is aberrant in alcohol-using youth.
Given the overlap of findings among these three studies, more work is needed to
confirm these results, with additional studies that focus on neurocognitive, alcohol
dose, and diagnostic severity relationships with hippocampal volume in alcohol-
using adolescents, as well as identification of premorbid risk-related abnormalities.
This appears to be a promising avenue of research for treatment studies that could
focus on improving memory encoding in adolescent alcohol users, or strengthening
memory functioning in youth at risk for future alcohol abuse.
2.2 FRONTAL LOBE

The PFC is one of the latest regions to undergo synaptic pruning and is responsible
for many higher-order executive functions that are developing during adolescence,
such as decision making, inhibitory control, working memory, selective attention,
and goal flexibility (for review, see Casey et al., 2000). Smaller overall PFC and
PFC white matter volumes have been demonstrated in youth with AUDs relative
to controls (De Bellis et al., 2005). Additionally, number of drinks in the largest
drinking episode was negatively correlated with PFC gray matter volume in these
youth. While gray matter volume reduction is characteristic of adolescent brain mat-
uration and may reflect normative synaptic pruning, excessive reduction may
represent an atypical trajectory of brain development. It will be important for future

studies to find neurocognitive correlates of this reduction in overall PFC volume in
youth with AUDs and to determine whether these results translate to studies of heavy
alcohol-using teens who do not meet criteria for an AUD diagnosis.
Another study that examined PFC volume in adolescents with AUDs divided the
PFC into posterior, anterior dorsal, and anterior ventral regions to understand spe-
cific PFC subregions that may be more affected in adolescents with AUDs
(Medina et al., 2008). The authors found an interesting sex-by-group interaction,
such that adolescent females with AUDs showed reductions in PFC gray and white
matter volume relative to female controls, driven by reduced anterior dorsal and an-
terior ventral PFC volumes, while males with AUDs showed the opposite effect, such
that they had larger PFC gray and white matter volumes relative to male controls, in
the same subregions. This striking interaction draws attention to an important area of
inquiry in the study of alcohol use’s effects on the adolescent brain—that is, are there
sex differences in the effects that alcohol has on brain structure, or different neural
risk features for adolescent alcohol use between the sexes?
Another sex-by-group interaction, reporting contrary patterns to the study above,
was shown in a study examining PFC cortical thickness, one contributor to gray mat-
ter volume, in adolescent binge drinkers (Squeglia et al., 2012b). In this study, male
binge drinkers had reduced PFC cortical thickness relative to nondrinking male
controls, but female binge drinkers had thicker prefrontal cortices compared with
nondrinking female controls. Increased prefrontal cortical thickness in females
was significantly related to poorer performance on a variety of neuropsychological
tests, including tests of attention, visuospatial processing, and inhibitory control.
Future studies with larger sample sizes will be needed to carefully study these inter-
actions, which could have major implications for addiction medicine, as health care
providers may need to design sex-specific treatment programs for adolescent alcohol
abusers.
The orbitofrontal cortex (OFC) is another frontal lobe region implicated in addic-
tion, as it has structural and functional connectivity with reward-related brain re-
gions, such as the nucleus accumbens (NAcc). A volumetric analysis of this
region in a large sample of juvenile justice-involved adolescents found that recent
drinking frequency was negatively related to OFC volume (Thayer et al., 2012).
It is uncertain whether these would be long term, persisting effects, or if abstinence
from alcohol use may diminish some of these effects, suggesting potential recovery
of brain regions.
One longitudinal investigation of alcohol-using adolescents with neuroimaging
data at both baseline and after alcohol use initiation found that cortical thickness
in the right middle frontal gyrus showed significantly larger decreases in youth
who had started using alcohol versus those who had not begun using (Luciana
et al., 2013). No premorbid differences in frontal lobe cortical thickness were present
between alcohol users and nonusers, further substantiating the possibility of an
alcohol-related effect. It will be important for future longitudinal studies to continue
to dissociate premorbid differences from those related to alcohol-induced changes in
2 Brain volume 219
brain development, particularly in groups matched over time for other potentially
confounding influences.
Another longitudinal study of current and future adolescent binge drinkers dem-
onstrated that ventromedial PFC and inferior frontal gyrus gray matter volume were
both smaller in current binge drinkers compared with controls, while smaller bilat-
eral superior frontal gyri volume was predictive of future binge drinking (Whelan
et al., 2014). These findings suggest that there may be dissociable regions of the
PFC reflecting vulnerability toward the consequences of alcohol use versus ability
to predict future onset of heavy use.
2.3 CEREBELLUM
A frequently reported site of alcohol-related brain damage in adults with AUDs has
been the cerebellum, and associated cerebellar motor deficits have been seen in this
population. In addition to its role in motor skills and balance, the cerebellum is also
integrated with frontal lobe circuitry, and frontocerebellar pathways are thought to be
critical to executive functioning (Schmahmann and Pandya, 1997). In a study by
De Bellis et al. (2005), where youth with AUDs had comorbid psychiatric disorders,
cerebellar volume was reduced in males with AUDs compared with controls—a find-
ing that was not present in females with AUDs. This then begs the question, is re-
duced cerebellar volume in males with AUDs related to motor or cognitive
deficits in those youth? Also, how much does the presence of other psychiatric dis-
orders account for these findings?
A study of cerebellar volume in binge-drinking youth without AUD diagnoses
found reduced cerebellar volume in binge drinkers relative to controls across both
male and female youth and reported a striking negative relationship between peak
number of drinks consumed in the past 3 months and cerebellar volume (Lisdahl
et al., 2013). This suggests a strong possibility, that in high doses, alcohol may have
a neurotoxic effect on the cellular architecture of the brain and that the cerebellum
should be a continued region of interest for future neuroimaging studies.
2.4 SUBCORTICAL STRUCTURES: BASAL GANGLIA, THALAMUS

Fewer studies in adolescent alcohol users have reported on brain morphometric
alterations of other brain regions, such as the basal ganglia and the thalamus. While
De Bellis et al. (2005) found no significant volumetric differences in the thalamus
between AUD youth and controls, a more recent study found that male youth with
AUDs and no comorbid psychiatric disorders had smaller thalamic volumes com-
pared with male controls, while female youth with AUDs had larger thalamic vol-
umes compared with female controls (Fein et al., 2013). This study was
conducted with voxel-based morphometry to measure gray matter density, while
the study by De Bellis et al. (2005) performed manual tracing of the thalamus. These
differences in methodology and the presence or absence of comorbidities could have
accounted for these discrepant findings. Further, the putamen is a motor structure of
the basal ganglia implicated in habit formation, and this area showed the same sex-
by-group interaction as reported for the thalamus, suggesting that basal ganglia struc-
ture may also be affected by heavy alcohol use during adolescence (Fein et al., 2013).
A recent longitudinal study reported basal ganglia volume change in binge drinkers
in the caudate, such that greater number of days of alcohol consumption was corre-
lated with larger reductions of caudate volume (Squeglia et al., 2014). Other regions,
such as the left ventral diencephalon, brain stem, and left inferior and middle
temporal gyrus, also showed brain volume reductions in youth who initiated heavy
alcohol use, but correlations with alcohol use were not present for these regions.
Finally, a study of the NAcc, the major dopamine output region of the mesolimbic
pathway, showed that past 3-month drinking frequency was positively associated
with the volume of this region (Thayer et al., 2012). This finding stands in contrast
to previously observed volumetric reductions in executive functioning brain cir-
cuitry, such as the PFC and cerebellum, in drinking adolescents. This could indicate
that heavy alcohol use leads to increases in volume of reward-related areas, but re-
ductions in volume of cognitive control regions, thereby altering neurocircuitry in
both bottom-up and top-down brain systems.
2.5 INSULA
The insula is a structure that has also been the focus of addiction research, as it is
implicated in internal emotional and bodily states that could be relevant for proces-
sing feelings associated with pleasure derived from or craving associated with sub-
stance use (Chung and Clark, 2014). This structure was the focus of a longitudinal
investigation in adolescents, a majority of whom had used alcohol and marijuana and
were in a treatment program for substance use (Chung and Clark, 2014). A mediation
model found a significant indirect effect between insular white matter volume and
binge-drinking frequency at baseline and 1 year into the study that was mediated
through enhancement motives for alcohol use. This suggests that the insula may
be a particularly good target for future studies aimed at understanding the neural
correlates of motivations for alcohol use that are linked with internal states.
3 WHITE MATTER MICROSTRUCTURE

3.1 ALCOHOL
Diffusion tensor imaging is able to indirectly infer information about water diffusion
along axons, with more restricted diffusion thought to reflect greater anisotropic
movement of water molecules along white matter fiber tracts. Higher fractional an-
isotropy (FA) and lower mean diffusivity (MD) are usually indicators of greater ax-
onal integrity and myelination, with higher FA and lower MD values seen across
development as white matter matures. A number of studies have specifically focused
on the effects of alcohol on white matter integrity during adolescence, while others
have had more mixed samples of adolescent substance users, including multisub-
stance or substance use disorder (SUD) histories, such as regular comorbid marijuana
and tobacco use.
3 White matter microstructure 221
In a study of binge-drinking adolescents, McQueeny et al. (2009) reported wide-

spread reductions in FA in many white matter tracts, including the superior longitu-
dinal fasciculus (SLF), corpus callosum, corona radiata, internal/external capsules,
commissural fibers, and the corticospinal tract. These results indicate that alcohol
may have global effects on white matter integrity that are not limited to specific
tracts. Many of the reductions in FA were related to greater prevalence of with-
drawal/hangover symptoms in these youth. However, two other studies of youth with
AUDs found higher FA in limbic tracts (Cardenas et al., 2013) and the corpus cal-
losum (De Bellis et al., 2008). The former study suggested that higher FA in white
matter tracts connecting reward and affect-related regions may be a risk marker for
drinking or perhaps greater integrity of these tracts reinforces alcohol use. In contrast
to those two studies, an investigation of juvenile justice-involved adolescents found
that youth with high scores on the Alcohol Use Disorders Identification Test had re-
duced FA in the SLF, which was related to higher impulsivity (Thayer et al., 2013).
Thus, it is plausible that lower FA may be present in white matter tracts involved with
regulatory functions, such as impulse control, while higher FA might be seen in
youth with AUDs in affect and reward-related connections, which could be driving
their propensity to consume alcohol.
One longitudinal investigation found that FA increased in the inferior fronto-
occipital fasciculus and dorsal caudate from baseline to follow-up in adolescents
who abstained from alcohol use for approximately 2 years, and this was driven by
decreases in radial diffusivity (diffusion of water perpendicular to the primary direc-
tion of diffusion along the white matter tracts; Luciana et al., 2013). These develop-
mental changes were not observed in the alcohol-using group, suggesting that white
matter maturation may have been blunted in these youth. It will be important to de-
termine the neurocognitive correlates of altered patterns of white matter maturation
during adolescence, especially with long-term continued alcohol use.
3.2 ALCOHOL AND MARIJUANA

Since a large proportion of adolescents use alcohol and marijuana, it becomes dif-
ficult to dissociate the effects of these substances on white matter integrity. In a study
of heavy alcohol and marijuana users compared with controls, widespread reductions
in FA were present across 10 different fiber tracts, including frontoparietal and tem-
poral lobe circuitry, in adolescent substance users compared with controls (Bava
et al., 2009). A few white matter tracts showed increased FA in users relative to con-
trols, and it is uncertain if these might be compensatory neuroadaptations due to
widespread reductions in white matter integrity among other regions. A follow-up
study in the same group of combined substance users and controls found that users
had poorer performance on processing speed, attention, and working memory that
were associated with lower FA in regions previously identified as having reduced
white matter integrity, such as the right inferior longitudinal fasciculus and superior
temporal lobe pathways (Bava et al., 2010). On the other hand, potential compensa-
tory changes might be present in occipital tracts where users had higher FA, which
was related to better visuomotor and verbal learning performance.
A study by Jacobus et al. (2009) used a three-group design with binge drinkers,
combined binge drinkers and marijuana users, and controls, to better dissociate the
effects of different substances on white matter integrity. While binge drinkers had
reductions in FA relative to controls in many long-range association tracts, such
as the superior and inferior longitudinal fasciculi, these same reductions in combined
alcohol and marijuana users were not present when compared with controls. These
surprising findings suggest that while binge drinking may be damaging to white
matter integrity, the combined effects of using multiple substances are not always
additive and may have different consequences for the maturation of white matter
during adolescence.
In some contrast to the findings above, the same research group conducted a lon-
gitudinal study with 16 adolescents and found that those youth who became heavy
alcohol and marijuana users by the time of their second study visit, 3 years later, had
lower FA compared with their baseline line scan, a decrease not present in those who
only initiated heavy alcohol use (Jacobus et al., 2013b). These results should be inter-
preted with caution, as the sample size for this study was fairly small; however, the
within individual change may be more informative than the above-referenced cross-
sectional design.
A longitudinal study of a larger sample of adolescent alcohol and marijuana users
found that escalation of substance use over a 1.5-year period was predictive of MD in
white matter tracts at follow-up, such as the SLF (Bava et al., 2013). Another lon-
gitudinal study that followed a group of controls, binge drinkers, and combined binge
and marijuana users over 3 years found reduced FA at the third neuroimaging visit in
users compared with controls (Jacobus et al., 2013a). Both substance-using groups
showed reductions in FA over the 3-year period, so in this case, binge drinking alone
as well as combined alcohol and marijuana use appeared to compromise FA. It is
important to note that these youth were in emerging adulthood (ages 19–22) at
the time of the third scan, so discrepancies between this finding and other studies
( Jacobus et al., 2009) could have been due to the age of the participants at the time
of the scan, as the effects of binge drinking and marijuana use on white matter
microstructure may depend on brain maturity.
Sex differences in alcohol’s effects on white matter microstructure also merit at-
tention, but few studies have specifically examined these differences. One study,
which replicated former results suggesting reduced integrity of SLF white matter
in adolescent alcohol users, also found a significant sex-by-group interaction, such
that females with SUDs had lower FA in this tract than males with SUDs, while fe-
male controls had higher FA in this tract than male controls (Thatcher et al., 2010).
These results should be interpreted with caution due to relatively small sample sizes,
and specificity to alcohol is uncertain given overlapping abuse and/or dependence of
multiple substances, as well as diagnoses of externalizing and internalizing disorders
in the SUD youth. It will be important for future studies to examine sex differences in
binge drinkers or youth with AUDs with no other significant substance use or
psychopathology.
4 Brain function 223
4 BRAIN FUNCTION
4.1 WORKING MEMORY
The most frequently studied neurocognitive function in alcohol-using adolescents
using functional magnetic resonance imaging (fMRI) has been working memory,
an executive function that improves across development and engages frontoparietal
circuitry, which matures during this time period (Crone et al., 2006). Working
memory-related brain response in adolescents who met criteria for AUDs was first
examined by Tapert et al. (2004b) using a visual working memory task. No differ-
ences in behavioral performance were present, but increased parietal and decreased
cerebellar, occipital, and temporal activity were seen in youth with AUDs. Addition-
ally, many brain regions showed both positive and negative relationships between
alcohol consumption variables, such as number of drinks consumed and withdrawal
symptoms. However, a study that examined sex-by-group interactions, albeit using a
different task, found very different patterns of brain response between female and
male youth with AUDs, which could have been masked in the former findings.
For example, in bilateral superior frontal gyri, females with AUDs showed decreased
spatial working memory (SWM)-related brain response, while males showed posi-
tive brain activity in these regions (Caldwell et al., 2005). Yet, in other areas, such as
the superior temporal lobes, females with AUDs showed greater response relative to
males with AUDs or the female controls. These complex interactions suggest that
heavy alcohol use may exert its influence on brain response very differently between
the sexes and among brain regions. Another study of SWM-related brain response in
adolescent binge drinkers showed that female binge drinkers had reduced SWM-
related brain activity in frontal lobe areas, such as the superior frontal gyrus, com-
pared with female controls, but male binge drinkers only showed elevated activity
relative to male controls in half of the regions in which interactions were found
(Squeglia et al., 2011). These findings could indicate a female sensitivity to alcohol’s
neurotoxic effects when consumed in high quantities, especially since poorer atten-
tion and working memory scores were related to reduced response in frontal and
cerebellar regions.
Another study by Tapert et al. (2004a) included youth with varying alcohol ex-
perience and administered a questionnaire to examine self-reported effects of alcohol
during initial use of the substance. Higher number of drinks needed to experience
effects was both positively and negatively related to working memory-related brain
response in superior frontal and superior parietal regions, respectively, which were
among many regions correlated with this measure. These results suggest that differ-
ent brain regions may be engaged by youth with varying levels of response to alco-
hol’s effects and could help establish neural markers of risk in adolescents who report
low levels of response to alcohol or neural markers that are protective in youth who
report less drinks needed to experience subjective effects.
The first longitudinal study of brain response in heavy alcohol users during a
working memory task examined group differences in heavy alcohol users versus
controls and also looked at baseline differences between these youth who later tran-
sitioned into heavy alcohol use versus those who continued to remain abstinent
across the 3-year period of the study. Greater frontoparietal activity was present
in heavy alcohol-using adolescents compared with controls, but at baseline, opposite
patterns were seen, such that in multiple regions, including the inferior parietal lobe,
brain response was lower in heavy drinkers compared with controls (Squeglia et al.,
2012a). It is possible that while normal neurodevelopmental trajectories are taking
place in healthy adolescents, altered neuromaturation in heavy alcohol users is lead-
ing to different patterns of brain response and that baseline neural phenotypes that
predict who goes on to use alcohol heavily may be very informative to preventing
heavy alcohol use in at-risk youth.
4.2 INHIBITORY CONTROL

Poor impulse control has been associated with alcohol abuse, and the neural corre-
lates of inhibitory control have been examined in adolescents who go on to use al-
cohol heavily. Using a longitudinal study design, Wetherill et al. (2013) examined
nogo versus go brain response in two groups of youth at baseline and 3 years later.
The controls remained low users, while the other group emerged into heavy drinking
by the time of the second study visit. Group-by-time interactions showed that at base-
line youth who later emerged into heavy alcohol use had lower middle frontal, infe-
rior parietal, and cerebellar tonsil brain activity, but higher brain response in these
regions at follow-up compared with controls. This complements other findings that
showed similar group-by-time interactions during a working memory task (Squeglia
et al., 2012a), which suggests overlapping patterns of brain activity during executive
functioning tasks at baseline and follow-up in youth who emerge into heavy alcohol
use. These results are also supported by another study of inhibitory control where
only baseline data were collected, but similar findings were seen showing less inhib-
itory control brain activity in PFC, parietal, and temporal regions in youth who later
emerged into heavy alcohol use compared with their peers (Norman et al., 2011).
4.3 VERBAL ENCODING

An fMRI study of binge-drinking youth showed increased frontoparietal activity
compared with controls during verbal encoding of word pairs, and no significant left
hippocampal activity while encoding words (Schweinsburg et al., 2010), a region
where volumetric reductions had been found previously in adolescents with AUD
(Nagel et al., 2005). The elevated frontoparietal response could indicate compensa-
tory changes in neural energetics or network efficiency in youth who use alcohol
heavily. Superior frontal and inferior parietal brain response was also elevated in
binge drinkers in a four-group design, with controls, users of alcohol or marijuana,
and adolescents who used both substances (Schweinsburg et al., 2011). Polysub-
stance users’ brain activity resembled that of controls, more so than use of either
substance alone, suggesting that use patterns and types of substances used are impor-
tant considerations for future studies even when groups are matched on task
performance.
4.4 DECISION MAKING AND REWARD PROCESSING

Adolescent heavy alcohol use may be associated with immature decision-making
abilities that lead to maladaptive risk taking. The Iowa gambling task is a
decision-making task that has been used in an fMRI study of binge drinkers and
showed that heavy alcohol users make more disadvantageous decisions on the task
than nonusers (Xiao et al., 2013). Significantly, elevated insular and amygdalar re-
sponse was present in binge drinkers during the task compared to controls, and in-
sular response was positively related to drinking problems and urgency scores, a
measure of impulsive behavior driven by negative emotions. These findings, similar
to altered insular white matter volume in heavy alcohol users, may indicate that
bottom-up affect-driven decision making may be related to risky behaviors, such
as binge drinking.
A comparison of current binge drinkers and controls that identified brain areas that
best differentiated the two groups via a machine learning analysis found that ventro-
medial PFC and inferior frontal gyrus activity were reduced during reward anticipa-
tion and consumption in binge drinkers compared with controls (Whelan et al., 2014).
While bottom-up decision making-related brain activity may be enhanced, these find-
ings suggest that reward evaluation may be compromised in heavy alcohol users.

A wealth of findings from structural (Tables 1 and 2) and functional (Table 3) neu-
roimaging studies of adolescent alcohol users indicates that a diagnosis of an AUD or
heavy alcohol use, in the absence of an AUD diagnosis, impacts brain volume, cor-
tical thickness, white matter microstructure, and brain activity. Reduced hippocam-
pal, PFC, and cerebellar volumes have all been reported in adolescent alcohol users,
while reward-related ventral striatal volumes have been shown to be increased. Sim-
ilarly, white matter integrity appears reduced in long-range association tracts con-
necting frontal and parietal regions, but increased in frontolimbic tracts. Working
memory-related and inhibitory control brain activity appears to be reduced prior
to heavy alcohol use in those who go on to binge drink, while being greater than
or at the level of controls in binge drinkers after heavy alcohol use. Binge drinkers
also show compensatory activity in frontoparietal regions during verbal encoding, in
the absence of hippocampal activity. Bottom-up emotion processing brain areas may
be hyperactive during affective decision making, while ventromedial PFC and infe-
rior frontal gyrus activity may be compromised during reward evaluation.
For many of these structural and functional brain imaging studies, sex-by-group
interactions are present, indicating a need for future research to examine these effects
Table 1 Brain Volume and Cortical Thickness Findings in Adolescent

Alcohol Users
Age
Range
Structure Study (Years) Population Main Findings
Hippocampus De Bellis et al. 13.5–21.0 N ¼ 12 AUD; #L and

(2000) N ¼ 24 C R hippocampal
volume in A
Nagel et al. 15–17 N ¼ 14 AUD; #L hippocampal
(2005) N ¼ 17 C volume in A
Medina et al. 15–18 N ¼ 16 A; #L hippocampal
(2007) N ¼ 26 A + M; volume and R > L
N ¼ 21 C asymmetry in A
Frontal lobe De Bellis et al. 13–21 N ¼ 14 AUD; #PFC and PFC white
(2005) N ¼ 28 C matter volume in A,
correlated with
alcohol use
Medina et al. 15–17 N ¼ 14 AUD, A females #avPFC
(2008) N ¼ 17 C volume, A males
"avPFC volume
Squeglia et al. 16–19 N ¼ 29 binge; A females thicker
(2012b) N ¼ 30 C L PFC cortices,
A males thinner L PFC
cortices
Thayer et al. 14–18 N ¼ 167 JJ OFC volume
(2012) adolescents negatively associated
with drinking
frequency
Luciana et al. 16–22 (at N ¼ 30 A; A "R MFG cortical
(2013) follow-up) N ¼ 25 C thickness loss at
follow-up
Whelan et al. 14 year N ¼ 115 binge; A #bilateral vmPFC,
(2014) olds N ¼ 150 C R inferior, and L MFG
volume
Cerebellum De Bellis et al. 13–21 N ¼ 14 AUD; A males #volume
(2005) N ¼ 28 C
Lisdahl et al. 16–19 N ¼ 46 Binge; Peak binge drinks in
(2013) N ¼ 50 C past 3 months
negatively related to
cerebellar gray matter
Thalamus De Bellis et al. 13–21 N ¼ 14 AUD; $Between A and C
(2005) N ¼ 28 C
Fein et al. 12–16 N ¼ 64 AUD; A males #thalamus
(2013) N ¼ 64 C volume; A females
"thalamus volume
Table 1 Brain Volume and Cortical Thickness Findings in Adolescent

Alcohol Users—cont’d
Age
Range
Structure Study (Years) Population Main Findings
Basal ganglia Thayer et al. 14–18 N ¼ 167 JJ NAcc volume
(2012) adolescents positively associated
with past 3-month
frequency of drinking
Fein et al. 12–16 N ¼ 64 AUD; A males #putamen
(2013) N ¼ 64 C volume; A females
"putamen volume
Squeglia et al. 15–21 (at N ¼ 20 heavy More lifetime alcohol
(2014) follow-up) drinkers; use negatively
N ¼ 20 C associated with left
caudate volume
reduction in A
Insula Chung and 14–18 N ¼ 30 drinkers Enhancement
Clark (2014) (14 with AUD) motives for alcohol
use mediated the
relationship between
insula white matter
volume and
frequency of past year
binge drinking
A, alcohol users; A + M, alcohol and marijuana users; AUD, alcohol use disorder; avPFC, anterior ventral
prefrontal cortex; C, controls; JJ, juvenile justice-involved adolescents; L, left; MFG, middle frontal gyrus;
NAcc, nucleus accumbens; OFC, orbitofrontal cortex; PFC, prefrontal cortex; R, right; vmPFC,
ventromedial prefrontal cortex; #, smaller or decreased; ", larger or increased; $, no difference.
more closely to develop sex-specific prevention and treatment strategies for adoles-
cent alcohol abusers. Furthermore, while comorbid alcohol and marijuana use may
limit our understanding of alcohol’s specific actions on brain structure and function,
multigroup study designs can aid with interpretation.
Importantly, since a majority of the previous research has been cross-sectional, it
is possible that many differences observed between heavy alcohol users and controls
may be premorbid and present prior to the onset of heavy alcohol use. This sugges-
tion is already supported by longitudinal studies indicating baseline differences in
brain response between adolescents who do and do not go on to use alcohol heavily
(Norman et al., 2011; Wetherill et al., 2013). Furthermore, neuroimaging studies of
at-risk youth with a FHP have shown overlapping findings to those described in this
chapter. For example, volumetric studies have found smaller parahippocampal gray
matter density in FHP nonalcohol-abusing adults (Sjoerds et al., 2013), while smaller
hippocampal volume has been reported in multiple studies of alcohol-abusing ado-
lescents (De Bellis et al., 2000; Medina et al., 2007; Nagel et al., 2005). This begs the
question of whether premorbid risk-related difference in hippocampal volume may
Table 2 White Matter Microstructure Findings in Adolescent Alcohol Users

Age
White Matter Range
Microstructure Study (Years) Population Main Findings
Alcohol De Bellis 13.3–19.3 N ¼ 32 AUD; A #MD, "FA in

et al. (2008) N ¼ 28 C isthmus region of
corpus callosum;
"FA in rostral body
of corpus callosum
in A
McQueeny 16–19 N ¼ 14 binge; A #FA across
et al. (2009) N ¼ 14 C 18 white matter
tracts (i.e.,
association,
commissural,
projection fibers);
some associated
with hangover
symptoms and
BAC
Thayer 14–18 N ¼ 125 JJ High AUDIT group
et al. (2013) adolescents have #FA in PCR,
R SLF; "FA in
R ACR
Luciana 16–22 (at N ¼ 30 A; N ¼ 25 C A #FA increase in
et al. (2013) follow-up) caudate and
inferior fronto-
occipital fasciculus
at follow-up
Cardenas Not N ¼ 50 AUD; "FA in limbic white
et al. (2013) reported N ¼ 50 C matter tracts
Alcohol Bava et al. 16–19 N ¼ 36 A + M; #FA in A + M in
+ marijuana (2009) N ¼ 36 C 10 regions (many
frontoparietal); "FA
in occipital, SLF,
internal capsule
Jacobus 16–19 N ¼ 14 binge; #FA in A across
et al. (2009) N ¼ 14 B + M; eight white matter
N ¼ 14 C tracts (i.e., L SCR);
in 4 of these
polysubstance
users "FA than A
Bava et al. 16–19 N ¼ 36 A + M; #FA in temporal
(2010) N ¼ 36 C regions associated
with poorer
working memory,
processing speed,
attention; "FA
related to better
verbal learning and
visuomotor skills
Table 2 White Matter Microstructure Findings in Adolescent Alcohol Users—

cont’d
Age
White Matter Range
Microstructure Study (Years) Population Main Findings
Thatcher 14–18 N ¼ 24 adolescents #FA in treatment
et al. (2010) entering treatment; group in SLF;
N ¼ 12 C females with SUD
#FA than males
with SUD;
C females "FA
than C males
Bava et al. 17–22 (at N ¼ 41 A + M; #FA in A in
(2013) follow-up) N ¼ 51 C R corpus
callosum,
prefrontal thalamic
fibers, PCR; "MD
and RD in many
tracts, including
SLF, PCR,
prefrontal thalamic
fibers
Jacobus 19–22 (at N ¼ 17 binge; #FA in A and A + M
et al. follow-up) N ¼ 21 B + M; across 14 white
(2013a) N ¼ 16 C matter tracts (i.e.,
corpus callosum,
ACR, SLF, UF,
SCR, internal
capsule)
Jacobus 19–22 (at N ¼ 8 heavy alcohol; #FA from baseline
et al. follow-up) N ¼ 8 heavy alcohol to follow-up in A
(2013b) +M + M in 12 tracts
(association,
projection,
interhemispheric
tracts); six tracts
"FA for A and #FA
for A + M
A, alcohol users; A + M, alcohol and marijuana users; ACR, anterior corona radiata; AUD, alcohol use
disorder; AUDIT, alcohol use disorders identification test; BAC, blood alcohol content; C, controls; FA,
fractional anisotropy; JJ, juvenile justice-involved adolescents; L, left; M, marijuana users; MD, mean
diffusivity; PCR, posterior corona radiata; PFC, prefrontal cortex; R, right; RD, radial diffusivity; SLF,
superior longitudinal fasciculus; SUD, substance use disorder; UF, uncinate fasciculus; #, smaller or
decreased; ", larger or increased.
Table 3 Brain Activity Findings in Adolescent Alcohol Users

Age
Range
fMRI Study (Years) Population Main Findings
Working Tapert et al. 15–17 N ¼ 35 alcohol Self-reported

memory (2004a) users response to alcohol
positively related to
superior and middle
frontal gyrus activity
Tapert et al. 15–17 N ¼ 15 AUD; A "parietal activity,
(2004b) N ¼ 19 C #precentral and
cerebellar response
Caldwell et al. 14–17 N ¼ 18 AUD; A x sex interaction in
(2005) N ¼ 21 C SFG; A females #than
A males or C females
Squeglia et al. 16–19 N ¼ 40 binge; A females #, A males
(2011) N ¼ 55 C "activity across
frontal, cingulate,
temporal, cerebellar
cortices
Squeglia et al. 12–16 N ¼ 20 heavy "Frontal and parietal
(2012a) (Study 2) drinkers; N ¼ 20 C activity from baseline
to follow-up in A, #in C
Inhibitory Norman et al. 12–14 N ¼ 21 transitioned #Activation at baseline
control (2011) (baseline) to heavy use; in transitioners in
N ¼ 17 C frontoparietal and
frontostriatal areas
during nogo
Wetherill et al. 12–17 N ¼ 20 binge; #Activation at baseline
(2013) (baseline) N ¼ 20 C in transitioners in
15–21 frontoparietal,
(follow-up) subcortical, cerebellar
regions during nogo;
"activation in
frontoparietal,
cerebellar regions at
follow-up
Verbal Schweinsburg 16–18 N ¼ 12 binge; "Activation in R SFG,
encoding et al. (2010) N ¼ 12 C bilateral posterior
parietal cortex,
#activation in occipital
cortex during novel
encoding in A
Schweinsburg 16–18 N ¼ 16 binge; #Inferior frontal;
et al. (2011) N ¼ 28 B + M; "dorsal frontal and
N ¼ 8 M; N ¼ 22 C parietal in A;
polysubstance users
resembled controls
References 231
Table 3 Brain Activity Findings in Adolescent Alcohol Users—cont’d

Age
Range
fMRI Study (Years) Population Main Findings
Decision Xiao et al. 16–18 N ¼ 14 binge; "L amygdala and
making/ (2013) N ¼ 14 C bilateral insula activity
reward in A during affective
decision making
Whelan et al. 14 year N ¼ 115 binge; #Activation in A in
(2014) olds N ¼ 150 C vmPFC, L IFG,
putamen, and
hippocampus during
reward anticipation;
#activation in vmPFC,
L IFG, R hippocampus
during reward receipt
A, alcohol users; AUD, alcohol use disorder; B + M, binge drinkers and marijuana users; C, controls; IFG,
inferior frontal gyrus; L, left; M, marijuana users; R, right; SFG, superior frontal gyrus; vmPFC,
ventromedial prefrontal cortex; #, smaller or decreased; ", larger or increased.
have contributed to previous hippocampal findings in alcohol-using youth. Addition-

ally, numerous studies have reported reduced FA across white matter tracts critical
for subserving executive functioning, such as the SLF, in both heavy alcohol users
(Jacobus et al., 2013a; McQueeny et al., 2009; Thatcher et al., 2010) and FHP youth
compared with controls (Acheson et al., 2014; Herting et al., 2010), suggesting pre-
morbid white matter microstructure deficits may heighten vulnerability toward alco-
hol abuse. On the other hand, it is possible that some differences between groups
represent developmental delays in brain maturation in adolescent alcohol users or
that some of these changes are reversible over time if alcohol use ceases. Ongoing
longitudinal research studies are critical to answer these questions and inform the
addiction medicine prevention and treatment community about neural risk factors
for alcohol use as well as the consequences of heavy alcohol use on neural structure
and functioning. Additionally, studies that can provide direct neurocognitive corre-
lates of these structural or functional phenotypes can be helpful in identifying strat-
egies where interventions are necessary to aid healthy cognitive functioning and
brain maturation during adolescence.
REFERENCES
Acheson, A., Wijtenburg, S.A., Rowland, L.M., Winkler, A.M., Gaston, F., Mathias, C.W.,
Fox, P.T., Lovallo, W.R., Wright, S.N., Hong, L.E., Dougherty, D.M., Kochunov, P.,
2014. Assessment of whole brain white matter integrity in youths and young adults with
a family history of substance-use disorders. Hum. Brain Mapp. 35, 5401–5413.
Bava, S., Frank, L.R., McQueeny, T., Schweinsburg, B.C., Schweinsburg, A.D., Tapert, S.F.,
2009. Altered white matter microstructure in adolescent substance users. Psychiatry Res.
173, 228–237.
Bava, S., Jacobus, J., Mahmood, O., Yang, T.T., Tapert, S.F., 2010. Neurocognitive correlates
of white matter quality in adolescent substance users. Brain Cogn. 72, 347–354.
Bava, S., Jacobus, J., Thayer, R.E., Tapert, S.F., 2013. Longitudinal changes in white matter
integrity among adolescent substance users. Alcohol. Clin. Exp. Res. 37 (Suppl. 1),
E181–E189.
Beresford, T.P., Arciniegas, D.B., Alfers, J., Clapp, L., Martin, B., Du, Y., Liu, D., Shen, D.,
Davatzikos, C., 2006. Hippocampus volume loss due to chronic heavy drinking. Alcohol.
Clin. Exp. Res. 30, 1866–1870.
Broadwater, M.A., Liu, W., Crews, F.T., Spear, L.P., 2014. Persistent loss of hippocampal
neurogenesis and increased cell death following adolescent, but not adult, chronic ethanol
exposure. Dev. Neurosci. 36, 297–305.
Caldwell, L.C., Schweinsburg, A.D., Nagel, B.J., Barlett, V.C., Brown, S.A., Tapert, S.F.,
2005. Gender and adolescent alcohol use disorders on BOLD (blood oxygen level depen-
dent) response to spatial working memory. Alcohol Alcohol. 40, 194–200.
Cardenas, V.A., Greenstein, D., Fouche, J.P., Ferrett, H., Cuzen, N., Stein, D.J., Fein, G., 2013.
Not lesser but Greater fractional anisotropy in adolescents with alcohol use disorders.
Neuroimage Clin. 2, 804–809.
Casement, M.D., Shaw, D.S., Sitnick, S.L., Musselman, S.C., Forbes, E.E., 2015. Life stress in
adolescence predicts early adult reward-related brain function and alcohol dependence.
Soc. Cogn. Affect. Neurosci. 10, 416–423.
Casey, B.J., Giedd, J.N., Thomas, K.M., 2000. Structural and functional brain development
and its relation to cognitive development. Biol. Psychol. 54, 241–257.
Chung, T., Clark, D.B., 2014. Insula white matter volume linked to binge drinking frequency
through enhancement motives in treated adolescents. Alcohol. Clin. Exp. Res.
38, 1932–1940.
Crone, E.A., Wendelken, C., Donohue, S., Van Leijenhorst, L., Bunge, S.A., 2006. Neurocog-
nitive development of the ability to manipulate information in working memory. Proc.
Natl. Acad. Sci. U.S.A. 103, 9315–9320.
Dawson, D.A., Goldstein, R.B., Chou, S.P., Ruan, W.J., Grant, B.F., 2008. Age at first drink
and the first incidence of adult-onset DSM-IV alcohol use disorders. Alcohol. Clin. Exp.
Res. 32, 2149–2160.
De Bellis, M.D., Clark, D.B., Beers, S.R., Soloff, P.H., Boring, A.M., Hall, J., Kersh, A.,
Keshavan, M.S., 2000. Hippocampal volume in adolescent-onset alcohol use disorders.
Am. J. Psychiatry 157, 737–744.
De Bellis, M.D., Narasimhan, A., Thatcher, D.L., Keshavan, M.S., Soloff, P., Clark, D.B.,
2005. Prefrontal cortex, thalamus, and cerebellar volumes in adolescents and young adults
with adolescent-onset alcohol use disorders and comorbid mental disorders. Alcohol. Clin.
Exp. Res. 29, 1590–1600.
De Bellis, M.D., Van Voorhees, E., Hooper, S.R., Gibler, N., Nelson, L., Hege, S.G.,
Payne, M.E., MacFall, J., 2008. Diffusion tensor measures of the corpus callosum in
adolescents with adolescent onset alcohol use disorders. Alcohol. Clin. Exp. Res.
32, 395–404.
Fein, G., Greenstein, D., Cardenas, V.A., Cuzen, N.L., Fouche, J.P., Ferrett, H., Thomas, K.,
Stein, D.J., 2013. Cortical and subcortical volumes in adolescents with alcohol dependence
but without substance or psychiatric comorbidities. Psychiatry Res. Neuroimaging
214, 1–8.
References 233
Giedd, J.N., Blumenthal, J., Jeffries, N.O., Castellanos, F.X., Liu, H., Zijdenbos, A., Paus, T.,
Evans, A.C., Rapoport, J.L., 1999. Brain development during childhood and adolescence:
a longitudinal MRI study. Nat. Neurosci. 2, 861–863.
Gogtay, N., Giedd, J.N., Lusk, L., Hayashi, K.M., Greenstein, D., Vaituzis, A.C., Nugent 3rd, T.F.,
Herman, D.H., Clasen, L.S., Toga, A.W., Rapoport, J.L., Thompson, P.M., 2004. Dynamic
mapping of human cortical development during childhood through early adulthood. Proc.
Natl. Acad. Sci. U.S.A. 101, 8174–8179.
Herting, M.M., Schwartz, D., Mitchell, S.H., Nagel, B.J., 2010. Delay discounting behavior
and white matter microstructure abnormalities in youth with a family history of alcohol-
ism. Alcohol. Clin. Exp. Res. 34, 1590–1602.
Hulvershorn, L.A., Cullen, K., Anand, A., 2011. Toward dysfunctional connectivity: a review
of neuroimaging findings in pediatric major depressive disorder. Brain Imaging Behav.
5, 307–328.
Jacobus, J., McQueeny, T., Bava, S., Schweinsburg, B.C., Frank, L.R., Yang, T.T., Tapert, S.F.,
2009. White matter integrity in adolescents with histories of marijuana use and binge drink-
ing. Neurotoxicol. Teratol. 31, 349–355.
Jacobus, J., Squeglia, L.M., Bava, S., Tapert, S.F., 2013a. White matter characterization of
adolescent binge drinking with and without co-occurring marijuana use: a 3-year investi-
gation. Psychiatry Res. 214, 374–381.
Jacobus, J., Squeglia, L.M., Infante, M.A., Bava, S., Tapert, S.F., 2013b. White matter
integrity pre- and post marijuana and alcohol initiation in adolescence. Brain Sci.
3, 396–414.
Johnston, L.D., O’Malley, P.M., Meich, R.A., Bachman, J.G., Schulenberg, J.E., 2015.
Monitoring the Future National Survey Results on Drug Use: 2014 Overview, Key Find-
ings on Adolescent Drug Use. Institute for Social Research, The University of Michigan,
Ann Arbor, MI.
King, S.M., Iacono, W.G., McGue, M., 2004. Childhood externalizing and internalizing psy-
chopathology in the prediction of early substance use. Addiction 99, 1548–1559.
Lieb, R., Merikangas, K.R., Hofler, M., Pfister, H., Isensee, B., Wittchen, H.U., 2002. Parental
alcohol use disorders and alcohol use and disorders in offspring: a community study.
Psychol. Med. 32, 63–78.
Lisdahl, K.M., Thayer, R., Squeglia, L.M., McQueeny, T.M., Tapert, S.F., 2013. Recent
binge drinking predicts smaller cerebellar volumes in adolescents. Psychiatry Res.
211, 17–23.
Luciana, M., Collins, P.F., Muetzel, R.L., Lim, K.O., 2013. Effects of alcohol use initiation on
brain structure in typically developing adolescents. Am. J. Drug Alcohol Abuse
39, 345–355.
Macpherson, L., Magidson, J.F., Reynolds, E.K., Kahler, C.W., Lejuez, C.W., 2010. Changes
in sensation seeking and risk-taking propensity predict increases in alcohol use among
early adolescents. Alcohol. Clin. Exp. Res. 34, 1400–1408.
McQueeny, T., Schweinsburg, B.C., Schweinsburg, A.D., Jacobus, J., Bava, S., Frank, L.R.,
Tapert, S.F., 2009. Altered white matter integrity in adolescent binge drinkers. Alcohol.
Clin. Exp. Res. 33, 1278–1285.
Medina, K.L., Schweinsburg, A.D., Cohen-Zion, M., Nagel, B.J., Tapert, S.F., 2007. Effects of
alcohol and combined marijuana and alcohol use during adolescence on hippocampal vol-
ume and asymmetry. Neurotoxicol. Teratol. 29, 141–152.
Medina, K.L., McQueeny, T., Nagel, B.J., Hanson, K.L., Schweinsburg, A.D., Tapert, S.F.,
2008. Prefrontal cortex volumes in adolescents with alcohol use disorders: unique gender
effects. Alcohol. Clin. Exp. Res. 32, 386–394.
Mills, K.L., Goddings, A.L., Clasen, L.S., Giedd, J.N., Blakemore, S.J., 2014. The develop-
mental mismatch in structural brain maturation during adolescence. Dev. Neurosci.
36, 147–160.
Nagel, B.J., Schweinsburg, A.D., Phan, V., Tapert, S.F., 2005. Reduced hippocampal volume
among adolescents with alcohol use disorders without psychiatric comorbidity. Psychiatry
Res. Neuroimaging 139, 181–190.
Norman, A.L., Pulido, C., Squeglia, L.M., Spadoni, A.D., Paulus, M.P., Tapert, S.F., 2011.
Neural activation during inhibition predicts initiation of substance use in adolescence.
Drug Alcohol Depend. 119, 216–223.
Schmahmann, J.D., Pandya, D.N., 1997. Anatomic organization of the basilar pontine projec-
tions from prefrontal cortices in rhesus monkey. J. Neurosci. 17, 438–458.
Schweinsburg, A.D., McQueeny, T., Nagel, B.J., Eyler, L.T., Tapert, S.F., 2010. A preliminary
study of functional magnetic resonance imaging response during verbal encoding among
adolescent binge drinkers. Alcohol 44, 111–117.
Schweinsburg, A.D., Schweinsburg, B.C., Nagel, B.J., Eyler, L.T., Tapert, S.F., 2011. Neural
correlates of verbal learning in adolescent alcohol and marijuana users. Addiction
106, 564–573.
Sjoerds, Z., Van Tol, M.J., Van den Brink, W., Van der Wee, N.J., Van Buchem, M.A.,
Aleman, A., Penninx, B.W., Veltman, D.J., 2013. Family history of alcohol dependence
and gray matter abnormalities in non-alcoholic adults. World J. Biol. Psychiatry
14, 565–573.
Squeglia, L.M., Schweinsburg, A.D., Pulido, C., Tapert, S.F., 2011. Adolescent binge drinking
linked to abnormal spatial working memory brain activation: differential gender effects.
Alcohol. Clin. Exp. Res. 35, 1831–1841.
Squeglia, L.M., Pulido, C., Wetherill, R.R., Jacobus, J., Brown, G.G., Tapert, S.F., 2012a.
Brain response to working memory over three years of adolescence: influence of initiating
heavy drinking. J. Stud. Alcohol Drugs 73, 749–760.
Squeglia, L.M., Sorg, S.F., Schweinsburg, A.D., Wetherill, R.R., Pulido, C., Tapert, S.F.,
2012b. Binge drinking differentially affects adolescent male and female brain morphom-
etry. Psychopharmacology (Berl.) 220, 529–539.
Squeglia, L.M., Rinker, D.A., Bartsch, H., Castro, N., Chung, Y., Dale, A.M., Jernigan, T.L.,
Tapert, S.F., 2014. Brain volume reductions in adolescent heavy drinkers. Dev. Cogn.
Neurosci. 9, 117–125.
Tapert, S.F., Pulido, C., Paulus, M.P., Schuckit, M.A., Burke, C., 2004a. Level of response to
alcohol and brain response during visual working memory. J. Stud. Alcohol 65, 692–700.
Tapert, S.F., Schweinsburg, A.D., Barlett, V.C., Brown, S.A., Frank, L.R., Brown, G.G.,
Meloy, M.J., 2004b. Blood oxygen level dependent response and spatial working memory
in adolescents with alcohol use disorders. Alcohol. Clin. Exp. Res. 28, 1577–1586.
Thatcher, D.L., Pajtek, S., Chung, T., Terwilliger, R.A., Clark, D.B., 2010. Gender differences
in the relationship between white matter organization and adolescent substance use disor-
ders. Drug Alcohol Depend. 110, 55–61.
Thayer, R.E., Crotwell, S.M., Callahan, T.J., Hutchison, K.E., Bryan, A.D., 2012. Nucleus
accumbens volume is associated with frequency of alcohol use among juvenile justice-
involved adolescents. Brain Sci. 2, 605–618.
References 235
Thayer, R.E., Callahan, T.J., Weiland, B.J., Hutchison, K.E., Bryan, A.D., 2013. Associations
between fractional anisotropy and problematic alcohol use in juvenile justice-involved ad-
olescents. Am. J. Drug Alcohol Abuse 39, 365–371.
Van Leijenhorst, L., Moor, B.G., Op de Macks, Z.A., Rombouts, S.A., Westenberg, P.M.,
Crone, E.A., 2010. Adolescent risky decision-making: neurocognitive development of
reward and control regions. Neuroimage 51, 345–355.
Wetherill, R.R., Squeglia, L.M., Yang, T.T., Tapert, S.F., 2013. A longitudinal examination of
adolescent response inhibition: neural differences before and after the initiation of heavy
drinking. Psychopharmacology (Berl.) 230, 663–671.
Whelan, R., Watts, R., Orr, C.A., Althoff, R.R., Artiges, E., Banaschewski, T., Barker, G.J.,
Bokde, A.L., Buchel, C., Carvalho, F.M., Conrod, P.J., Flor, H., Fauth-Buhler, M.,
Frouin, V., Gallinat, J., Gan, G., Gowland, P., Heinz, A., Ittermann, B., Lawrence, C.,
Mann, K., Martinot, J.L., Nees, F., Ortiz, N., Paillere-Martinot, M.L., Paus, T.,
Pausova, Z., Rietschel, M., Robbins, T.W., Smolka, M.N., Strohle, A., Schumann, G.,
Garavan, H., 2014. Neuropsychosocial profiles of current and future adolescent alcohol
misusers. Nature 512, 185–189.
Xiao, L., Bechara, A., Gong, Q., Huang, X., Li, X., Xue, G., Wong, S., Lu, Z.L., Palmer, P.,
Wei, Y., Jia, Y., Johnson, C.A., 2013. Abnormal affective decision making revealed in
adolescent binge drinkers using a functional magnetic resonance imaging study. Psychol.
Addict. Behav. 27, 443–454.
CHAPTER
Neuroscience of opiates
From stress-responsive
systems to behavior
12
Yan Zhou*,1, Francesco Leri†
*The Laboratory of the Biology of Addictive Diseases, The Rockefeller University,
New York, NY, USA
†
Department of Psychology, University of Guelph, Guelph, ON, Canada
1
Abstract
Opiate addiction, similarly to addiction to other psychoactive drugs, is chronic relapsing brain
disease caused by drug-induced short-term and long-term neuroadaptations at the molecular,
cellular, and behavioral levels. Preclinical research in laboratory animals has found important
interactions between opiate exposure and stress-responsive systems. In this review, we will
discuss the dysregulation of several stress-responsive systems in opiate addiction: vasopressin
and its receptor system, endogenous opioid systems (including proopiomelanocortin/mu opi-
oid receptor and dynorphin/kappa opioid receptor), orexin and its receptor system, and the
hypothalamic–pituitary–adrenal axis. A more complete understanding of how opiates alter
these stress systems, through further laboratory-based studies, is required to identify novel
and effective pharmacological targets for the long-term treatment of heroin addiction.
Keywords
Stress, HPA axis, Vasopressin, V1b receptor, Dynorphin, POMC, Opioid receptor, Orexin,
Heroin addiction
Abbreviation
AVP arginine vasopressin
CPP conditioned place preference
CRF corticotropin-releasing factor
CRF-R1 CRF type I receptor

237
238 CHAPTER 12 Opiates with brain stress-responsive and HPA systems
eGFP enhanced green fluorescent protein

HPA hypothalamic–pituitary–adrenal
KOP-r kappa opioid receptor
MOP-r mu opioid receptor
NAc nucleus accumbens
nor-BNI nor-binaltorphimine
POMC proopiomelanocortin
pPVN parvocellular division of PVN
PVN paraventricular nucleus
V1b AVP type 1b receptor
VTA ventral tegmental area
1 INTRODUCTION
Opiate addiction is a major global public health problem, and there is still a need for
alternative medications that could enhance the effectiveness of existing treatments
(e.g., methadone maintenance treatment) in reducing opiate abuse, manage with-
drawal, and prevent relapse. Addiction to heroin, a potent agonist at opioid receptors,
is often characterized by a drug user’s initial use resulting in tolerance and eventually
severe withdrawal symptoms during periods of abstinence. The reward pathways and
withdrawal symptoms, and the desire to avoid them often result in relapse and rees-
calation of drug use. The length of time a person spends in each of the different de-
veloping stages of opiate addiction varies by individual; stress plays a major role in
initiation, maintenance, and withdrawal, and elevates drug craving (Koob and
Kreek, 2007).
Recent studies in laboratory animals have implicated the dysregulation of several
brain stress-responsive systems and hypothalamic–pituitary–adrenal (HPA) axis in
the acquisition of opiate self-administration behaviors and progression toward opiate
dependence. For example, environmental stressors modulate the effects of drugs on
the acquisition of drug self-administration behavior, locomotor activity, and rein-
statement of self-administration after extinction (e.g., Breese et al., 2011; Heilig
et al., 2010; Koob and Kreek, 2007; Schank et al., 2012; Shalev et al., 2010;
Sinha et al., 2011; Spanagel et al., 2014). Atypical stress responsivity is one of
the critical factors influencing individual vulnerability to drug relapse. This review
will discuss the roles of four important systems to current addiction research.
The arginine vasopressin (AVP) system has been studied in neuroendocrinology
and drug addiction. The HPA axis in rodents is directly influenced by the AVP sys-
tem. This neuropeptide system is profoundly altered by opiates in rodent models,
which is discussed in detail in this review. Of interest is the impact of drugs of abuse,
such as heroin, alcohol, and cocaine, on AVP and V1b (AVP type 1b receptor) sys-
tem and their potential roles in taking and seeking behaviors. Specific brain areas
such as the medial amygdala, paraventricular nucleus (PVN) of the hypothalamus,
and anterior pituitary will be discussed as well as the functions of AVP and its
V1b receptors which have been identified and elucidated.
2 AVP and V1b systems 239
The endogenous opioid systems include the proopiomelanocortin (POMC)/mu

opioid receptor (MOP-r) and dynorphin/kappa opioid receptor (KOP-r) systems.
The new data on potential roles of POMC and dynorphin in opiate-related
seeking behaviors and the control of the HPA axis will be discussed herein as the
second topic.
The third is the stress-responsive orexin (or hypocretin) system. Most of the lat-
eral hypothalamic orexin neurons coexpress dynorphin. Orexin has actions in
reward-related areas of the brain, such as the nucleus accumbens (NAc) and ventral
tegmental area (VTA) with implications in rewarding and addictive-like behaviors.
Finally, there is substantial evidence demonstrating that opiates alter the HPA
axis, and in turn the abnormal HPA activity may contribute to the development of
opiate addiction and relapse to drug use. In our discussion of the four systems, we
will provide an overview of recent research on opiate addiction, with specific em-
phasis on preclinical laboratory-based research to elucidate the neurobiology of opi-
ate addiction.
2 AVP AND V1B SYSTEMS

The two central G protein-coupled AVP receptor subtypes V1a and V1b are highly
expressed in the rat extended amygdala. The V1b receptors are expressed promi-
nently in the amygdala, hypothalamus, hippocampus, and anterior pituitary. Recent
studies suggest that increased AVP neuronal activity in the amygdala represents a
step in the neurobiology of stress-related behaviors in rodent models: (a) acute stress
increases extracellular AVP levels in the rat amygdala (Wigger et al., 2004) and
(b) activation of AVP V1b receptors underlies anxiety-like and depression-like be-
haviors (Griebel et al., 2002; Roper et al., 2011; Salome et al., 2006; Serradeil-Le
Gal et al., 2002).
In order to examine the role of AVP in heroin addiction, the expression of the
AVP gene in the rat amygdala and hypothalamus was studied after chronic intermit-
tent escalating-dose heroin or during early and late spontaneous withdrawal. AVP
mRNA levels expressed in the medial amygdala were increased during early heroin
withdrawal (Zhou et al., 2008a). To further study the AVP system in response to
stress, we designed experiments using unpredictable foot shock, a widely used stim-
ulus to elicit stress responses in rodents. Foot-shock stress was found to increase
AVP mRNA levels in the medial amygdala in rats trained to self-administer heroin
(in comparison with the nonshock rats self-administering heroin and the rats with
saline self-administration), suggesting that AVP sensitivity to stress is increased after
voluntary heroin exposure. It was also investigated whether blockade of central AVP
receptors (V1a or V1b receptor) would attenuate the reinstatement of heroin-seeking
behavior by foot-shock stress, and HPA hormonal responses to foot shock. The
selective V1b receptor antagonist SSR149415 (but not the relatively selective V1a
antagonist) dose-dependently attenuated foot shock-induced reinstatement of heroin
seeking and lowered foot shock-induced HPA activation (Zhou et al., 2008a).
Additionally, increased AVP mRNA levels in the medial amygdala were also
found after acute withdrawal from chronic cocaine exposure (Zhou et al.,
2005). Together, these data suggest that stress-responsive AVP/V1b receptor sys-
tems in the medial amygdala may be critical components of the neural circuitry
underlying the effect of aversive emotional states, such as drug withdrawal, on
drug-seeking behavior (Brown and Lawrence, 2009; D’Souza and Markou,
2010; Zhou et al., 2008a).
Additionally, to investigate the involvement of AVP and V1b in alcohol drinking
behavior, we used genetically selected Sardinian alcohol-preferring (sP) rats
(Colombo et al., 2006), in collaboration with the Colombo laboratory at C.N.R. In-
stitute of Neuroscience at the University of Cagliari in Italy, and found that pharma-
cological blockade of V1b receptor reduced alcohol consumption in sP rats (Zhou
et al., 2011a). This is consistent with the observation that the selective V1b receptor
antagonist SSR149415 dose-dependently reduced excessive levels of alcohol self-
administration in alcohol-dependent Wistar rats (induced by chronic intermittent
alcohol vapor exposure) without affecting the limited levels of alcohol drinking in
nondependent rats (Edwards et al., 2012).
Interestingly, higher basal levels of AVP mRNA are found in the PVN of
Indiana alcohol-preferring and high-alcohol drinking rats, when compared to
alcohol-nonpreferring and low-alcohol drinking rats. Our recent studies on selec-
tively bred Sardinian alcohol-preferring versus Sardinian alcohol-nonpreferring
rats showed similar results: Sardinian alcohol-preferring rats display higher basal
AVP mRNA levels in the PVN and medial amygdala than Sardinian alcohol-
nonpreferring rats, and voluntary alcohol consumption decreased the AVP mRNA
levels in both the PVN and medial amygdala of Sardinian alcohol-preferring rats
(Zhou et al., 2011a).
Earlier studies have shown that AVP in the parvocellular division of PVN
(pPVN) does not contribute to the acute stimulatory effects of cocaine on HPA ac-
tivity. However, we recently found persistent elevations of both peripheral plasma
ACTH levels and AVP mRNA levels in the pPVN of the rats after 14 days of pro-
tracted cocaine withdrawal, and V1b antagonists attenuated cocaine withdrawal-
induced HPA activation (Zhou et al., 2011b). Interestingly, in AVP-enhanced green
fluorescent protein (eGFP) transgenic mice, cocaine withdrawal increased the num-
ber of pPVN AVP neurons expressing GFP, further confirming that enhanced pPVN
AVP gene expression is associated with persistent elevations of basal HPA activity.
These results indicate that AVP and its receptor system are involved in chronic stress
and may be an attractive therapeutic target for treating anxiety and depressive symp-
toms associated with withdrawal from drugs of abuse. Hence, it may be important
to explore the value of both the V1b and V1a receptor antagonists in the management
of opiate, cocaine, or alcohol abuse and relapse (Bisagno and Cadet, 2014; Koob,
2008; Koshimizu et al., 2012; See and Waters, 2010). Also, though AVP is a potent
modulator of stress, further studies should clarify the specific involvement of
AVP and V1b receptor systems in relapse-like behaviors after chronic withdrawal
from drugs.
3 Endogenous opioid systems 241
3 ENDOGENOUS OPIOID SYSTEMS

3.1 POMC SYSTEMS
The POMC gene encodes a prohormone expressed at significant levels in the
pituitary or specific brain regions. Cell-specific posttranslational processing of
the POMC prohormone generates a variety of biologically active peptides. In the
pituitary, anterior lobe corticotrophs release ACTH, whereas intermediate lobe mel-
anotrophs further process POMC to produce N-acetylated forms of a-melanocyte-
stimulating hormone and b-endorphin. In the brain, a specialized population of
neurons in the hypothalamic arcuate nucleus expresses POMC, giving rise to
a-, b-, and g-melanocortins and the potent opioid peptide beta-endorphin (e.g.,
Cowley et al., 2001; Rubinstein et al., 1996). Beta-endorphin, primarily acting on
MOP-r, is mainly expressed in the hypothalamic POMC neurons, the principal clus-
ter of POMC/beta-endorphin neurons in the brain. It is known that activation of
MOP-r by beta-endorphin results in positive affective reactions and is rewarding
in rats, possibly by modulation of DA cells in the VTA and associated release of
DA in the NAc (e.g., Spanagel et al., 1991). Hence, it is hardly surprising that
beta-endorphin is involved in the motivational and affective actions of most drugs
of abuse. Dopamine D2-like receptors are involved in regulation of POMC gene ex-
pression in the hypothalamus (Zhou et al., 2004). The selective D2 antagonist sulpir-
ide increased POMC mRNA levels in the hypothalamus, indicating that D2-like
receptors exert tonic inhibitory effect on hypothalamic POMC gene expression.
Blockade by a selective D1-like receptor antagonist SCH23390 had no effect on hy-
pothalamic POMC mRNA levels, suggesting a specific role for the D2 receptors in
hypothalamic POMC expression.
Heroin, morphine, and other short-acting opiates regulate the activity of endog-
enous opioid systems. In rats, chronic intermittent heroin administration by experi-
menters (Zhou et al., 2013c) or chronic heroin self-administration (Zhou et al., 2015)
resulted in decreased POMC mRNA levels in the hypothalamus during acute (1 day)
withdrawal or after 9 days of withdrawal, respectively, suggesting a hypothesis that
long-term exposure to opiates leads to relative deficiency in beta-endorphin system
(Negus and Rice, 2009). In parallel, there is an upregulation of MOP-r mRNA ex-
pression levels after acute opiate withdrawal in NAc, caudate-putamen, and lateral
hypothalamus, indicating a compensatory increase in MOP-r biosynthesis due to the
less beta-endorphin (Le Merrer et al., 2009; Zhou et al., 2006). The presumed relative
deficiency in endogenous beta-endorphin (as reflected by decreased POMC mRNA
levels in the hypothalamus) could lead to a hyperactive HPA axis and corresponding
increases in hormone secretion during spontaneous opiate withdrawal. Indeed, in-
creases in HPA hormonal levels have been observed in rats during acute spontaneous
opiate withdrawal (Ignar and Kuhn, 1990; Martinez et al., 1990; Zhou et al., 2006).
POMC-derived peptides, especially beta-endorphin, are also distributed in the
dopaminergic mesocorticolimbic regions, including the NAc, VTA, and frontal cor-
tex. In addition to the arcuate nucleus, POMC mRNA has also been detected in the
NAc and dorsal striatum at relatively low levels. Therefore, the demonstration of
POMC neuron distribution in the NAc region is an essential issue concerning the
neural networks containing POMC mRNA and derived peptides in the NAc. Using
POMC-eGFP transgenic mice in which POMC-expressing neurons were labeled
with eGFP and enhanced by immunohistochemistry procedures, we found that
POMC-eGFP-expressing neurons are present in modest amounts in the NAc core,
shell, and dorsal striatum of POMC-eGFP mice (Zhou et al., 2013a).
We also measured POMC mRNA levels in these two subdivisions of NAc and the
dorsal striatum of Sardinian alcohol-preferring (sP) rats exposed to 17-day alcohol
drinking and found that voluntary consumption of high amounts of alcohol by sP rats
was associated with increases in POMC mRNA levels in the NAc shell, but not NAc
core. This result suggests that voluntary alcohol drinking modulates POMC mRNA
expression in the POMC neuron populations in the NAc shell. The POMC neurons in
the shell are a region long considered to mediate processes of reward and reinforce-
ment (e.g., Di Chiara, 2002), and our results support their role in alcohol intake in this
model (Zhou et al., 2013a). Several studies have also demonstrated that alcohol, co-
caine, or cannabinoids are self-administered directly into the NAc shell, but not the
core (e.g., Rodd-Henricks et al., 2002). Therefore, the shell (not the core) may be the
region in which alcohol and other drugs of abuse contribute to reinforcing effects
mediated through the POMC neuronal activation. The potential involvement of
NAc POMC in heroin- or cocaine-related behaviors needs further investigation.
3.2 DYNORPHIN SYSTEMS

Activation of the dynorphin/KOP-r systems has been implicated in the negative rein-
forcement aspects of opiate, alcohol, and psychostimulant addictions (Bodnar, 2014;
Koob and Kreek, 2007). As there is more recent progress on the dynorphin/KOP-r
systems in alcohol research, we highlight some relevant findings below. In rats, acute
administration of KOP-r agonists attenuates alcohol self-administration and decreases
alcohol-induced conditioned place preference (CPP), while the selective KOP-r antag-
onist nor-binaltorphimine (nor-BNI) increased alcohol drinking in rats with high basal
levels of alcohol consumption. KOP-r agonists inhibit GABAergic synaptic responses
and alcohol effects in the central nucleus of amygdala and bed nucleus of the stria ter-
minalis (Li et al., 2012), which may be the mechanism by which these agonists can
modulate responses to alcohol and possibly other addictive drugs. Recently, KOP-r
antagonists have also been reported to attenuate alcohol-seeking behavior induced
by stress in mice (Sperling et al., 2010) and to reduce alcohol consumption in
alcohol-dependent rats (Walker and Koob, 2008).
Dynorphin and KOP-r systems in the NAc shell have been implicated in the mod-
ulation of drug escalation and seeking behaviors (Nealey et al., 2011; Schlosburg
et al., 2013; Zhou et al., 2013b). In fact, KOP-r antagonists administered in the shell
reduce alcohol consumption in alcohol-dependent rats (Nealey et al., 2011) as well as
escalation of heroin intake in dependent rats (Schlosburg et al., 2013). Interestingly,
4 Orexin and its receptors 243
heroin seeking induced by stress is associated with increased dynorphin mRNA

levels in this region (Zhou et al., 2013b).
Laboratory studies in humans have found that yohimbine increased subjective
anxiety in normal subjects and drug craving in abstinent opiate addicts (Stine
et al., 2002). Yohimbine enhances central noradrenergic activity by acting as an an-
tagonist at alpha-2 adrenergic autoreceptors and reinstates heroin, methamphet-
amine, cocaine, alcohol, and food seeking. Of interest, the pretreatment with
KOP-r antagonist nor-BNI blocked the heroin-seeking behavior induced by food
deprivation stress (Sedki et al., 2015), or yohimbine stress (Zhou et al., 2013b),
and attenuated escalation of heroin taking (Schlosburg et al., 2013). In line with these
findings, blockade of KOP-r also attenuated naltrexone-precipitated withdrawal and
conditioned place aversion in morphine-dependent rats, suggesting that KOP-r acti-
vation is involved in opiate withdrawal, its aversive consequences, and probably con-
sequent relapse (Kelsey et al., 2015).
In tissue plasminogen activator (tPA, endogenous microglia activator) knockout
mice, basal levels of dynorphin (but not KOP-r or enkephalin) mRNA are increased
in the NAc (Maiya et al., 2009). It has been demonstrated that NAc dialysate dopa-
mine levels are decreased after stimulation of KOP-r ((Spanagel et al., 1990). On
the basis of this evidence, it has been hypothesized that increased basal levels of
dynorphin in the NAc may lead to altered dopaminergic signaling after drug expo-
sure. Indeed, cocaine-induced CPP and locomotor sensitization, as well as cocaine
withdrawal-induced stress responses (CRF mRNA increases in the amygdala), are
attenuated in tPA knockout mice (Maiya et al., 2009; Zhou et al., 2010). Our work
also indicates a potential involvement of microglial systems in regulation of NAc
dynorphin/KOP-r responsivity to drug reward, as tPA deletion resulted in a defi-
ciency of endogenous microglia activation (Maiya et al., 2009).
As mentioned above, we have learned a great deal from selective animal models
regarding POMC/MOP-r and dynorphin/KOP-r systems, focusing on the neurobiol-
ogy of heroin addiction. The MOP-r and KOP-r are attractive therapeutic targets for
treating opiate addiction.
4 OREXIN AND ITS RECEPTORS

The orexins are expressed in the lateral hypothalamus, perifornical area, and dor-
somedial hypothalamus, with extensive projections in the brain (de Lecea et al.,
1998). Orexin A acts at orexin type 1 and 2 receptors (OX1R and OX2R), and orexin
B acts on OX2R exclusively. Hypothalamic orexins are involved in the regulation of
sleep–wakefulness, arousal, feeding, and stress. Orexin receptor blockade in the
VTA after acute morphine administration, for example, attenuated an increase in ex-
tracellular dopamine levels in the NAc (Narita et al., 2006), and orexins and orexin
receptor interactions have been found to trigger morphine-motivated behaviors
(Harris et al., 2005; Sharf et al., 2010; Smith and Aston-Jones, 2012), suggesting that
orexins have a role in the modulation of drug reward and drug-seeking behaviors
(Baimel et al., 2015; Boutrel et al., 2010; Calipari and España, 2012; Yeoh et al.,
2014), and OX1R antagonists could have medication potential in opioids of abuse
(Harris et al., 2005).
During the aversive state of acute opiate withdrawal, orexin neuronal activity and
mRNA levels are increased in the lateral hypothalamus, indicating that the increased
orexin neuronal activity could contribute to negative affective states in opiate with-
drawal (Georgescu et al., 2003). Because most of the lateral hypothalamic orexin
neurons coexpress the dynorphin gene (Chou et al., 2001), we examined levels of
both the orexin and dynorphin mRNAs in the lateral hypothalamus, and found that
orexin mRNA levels were increased in rat lateral hypothalamus, but the dynorphin
mRNA levels remain unaltered in the lateral hypothalamus in acute withdrawal from
chronic escalating-dose morphine (Zhou et al., 2006). To investigate whether this
observation held true with other drugs of abuse, we extended our research to cocaine.
We were primarily interested in investigating whether orexin or dynorphin mRNA
levels in rat lateral hypothalamus or medial hypothalamus (perifornical and dor-
somedial areas) are altered by acute cocaine withdrawal (Zhou et al., 2008b). Similar
to morphine withdrawal, acute withdrawal from chronic escalating-dose cocaine ad-
ministration also resulted in increased orexin mRNA levels in the lateral hypothal-
amus, but not the medial hypothalamus. In contrast to the opiate withdrawal, acute
cocaine withdrawal also increased the dynorphin mRNA levels in the lateral hypo-
thalamus (Zhou et al., 2008b). These results suggest that the orexin expression alter-
ation in response to drug withdrawal seems lateral hypothalamus-specific. Orexin
and dynorphin in the lateral hypothalamus may differentially contribute to the en-
hanced negative affective states in opiate and cocaine withdrawal.
Modafinil is a stimulant used to treat narcolepsy and other disorders involving
excessive sleepiness. Because of its long-acting stimulatory action on orexin, central
monoamine, and glutamate systems (Minzenberg and Carter, 2008), modafinil was
investigated as a potential “substitution” treatment for cocaine dependence, with-
drawal, and relapse. We employed Sprague–Dawley rats trained to self-administer
cocaine to explore whether chronic administration of modafinil (0, 25, or 50 mg/kg,
IP, twice daily) could alter spontaneous cocaine seeking observed during extinction,
and reinstatement of cocaine seeking precipitated by foot-shock stress (Leri et al.,
2009). In parallel, two additional experiments were performed to assess the effect
of cocaine sensitization (20 mg/kg 5 days) on the stimulatory and rewarding
(CPP) effects of modafinil (50 and 100 mg/kg). In the reinstatement study, it was found
that modafinil did not alter responding during extinction or during the test of reinstate-
ment induced by exposure to foot-shock stress. In the locomotion cross-sensitization
experiment, it was found that the stimulatory properties of modafinil were significantly
increased by chronic cocaine exposure, but cocaine sensitization did not enhance the
rewarding properties of modafinil. Finally, in all experiments, modafinil enhanced the
effects of cocaine exposure on elevations of orexin mRNA expression in the lateral
hypothalamus. Interestingly, it has been reported that cue-induced relapse could be
blocked by OX1 receptor antagonist SB334867 (Kallupi et al., 2010). Therefore, these
results in laboratory rats do not support the effectiveness of modafinil in preventing
5 HPA axis 245
relapse to cocaine seeking caused by stress, and further suggest that modafinil may
have enhanced stimulatory properties in cocaine addicts. Moreover, the blockade of
orexin system rather than its activation could be an efficacious strategy for the treat-
ment of cocaine abuse and, because modafinil tends to enhance mRNA production of
orexin, it is possible that this drug may be a safe pharmacological approach only the
alleviation of cocaine withdrawal (Leri et al., 2009).
5 HPA AXIS
It has been reported that stress-induced elevation of HPA activity predicts relapse to
drug use and amounts of subsequent use (e.g., Sinha et al., 2006). Vulnerability to
drug abuse is enhanced by stress, and the HPA response to stress seems one of
the critical factors influencing individual vulnerability to drug abuse. The HPA axis
is a well-studied stress-responsive system in animals and humans. Stress, triggered
by internal or external stimuli, increases corticotropin-releasing factor (CRF) and
AVP, causing their release into the pituitary portal circulation from terminals of
hypothalamic PVN. Activation of CRF type I receptor (CRF-R1) and V1b stimulates
the release of the POMC peptides (Vale et al., 1981). Two major POMC gene
products are ACTH and beta-endorphin (39 and 31 amino acids, respectively).
Acting primarily on the adrenal cortex, ACTH releases corticosterone in rodents.
Glucocorticoids, which are essential for life in mammals, act in a negative feedback
mood by decreasing biosynthesis, release, and function of CRF and AVP in the
hypothalamus and of CRF-R1 and V1b receptors in the anterior pituitary. Glucocor-
ticoids also act to reduce the processing and release of POMC peptides in the anterior
pituitary.
In early studies, an acute opiate challenge had a stimulatory effect on plasma
ACTH and corticosterone release in opiate-naı̈ve mice and rats. After chronic opiate
administration from 1 to 2 weeks, however, the HPA axis was not activated by heroin
or morphine but rather it was suppressed (Zhou et al., 2008a, 2013c). Chronic expo-
sure to short-acting opiates acts as chronic stressor by virtue of the withdrawal that
occurs between every exposure, and it may alter the responsivity of the HPA axis, as
do many other stressors (e.g., Houshyar et al., 2003). Indeed, a low dose of heroin
challenge decreased ACTH levels in rats during chronic withdrawal after HPA hor-
monal levels returned to baseline, which is in contrast to the stimulatory effect of
acute heroin in opiate-naı̈ve animals (Zhou et al., 2013c). The effects of opiates
on HPA activity also depend on the presence or absence of external stressors, al-
though the mechanisms responsible for this interaction are not well understood. In
support of this concept, it was found that while either acute morphine or stress alone
increased ACTH levels as an independent stimulus, morphine decreases plasma
ACTH levels elevated by the stress (Zhou et al., 2013c). Together, animal studies
demonstrate that morphine, heroin, or other short-acting opiates reduce HPA activity
caused by stress, indicating that opioids act in a counter-regulatory role in modulat-
ing HPA stress responsivity under stress conditions.
Recent findings demonstrated that in comparison with saline or water controls, an

abnormal HPA activity (including an enhanced dexamethasone–CRF response and
increased basal hormonal levels) was found in mice and rats during chronic alcohol
or cocaine withdrawal with an increased AVP mRNA level or a decreased CRF
mRNA level (Pang et al., 2013; Zhou et al., 2011b). However, few studies have spe-
cifically addressed the involvement of AVP and V1b receptor systems in the HPA
modulation and relapse-like behavior after chronic withdrawal from long-term opi-
ate exposure, though AVP is a potent modulator of brain stress-responsive systems
and HPA axis.
Studies in animals and humans have also demonstrated that beta-endorphin and
dynorphin exert tonic inhibition and stimulation of HPA activity by acting on the
MOP-r and the KOP-r, respectively. For instance, beta-endorphin acting on the
MOP-r exerts tonic inhibition of CRF and then of the HPA axis in rodents. KOP-r
agonists stimulate plasma corticosterone levels in rats. The stimulatory effects of
the KOP-r agonists on the HPA axis were blocked by selective KOP-r antagonist
nor-BNI. Consistent with the evidence that dynorphin/KOP-r modulates stress
via the HPA axis, recent work further found that the yohimbine-induced or food
restriction stress-induced HPA activation was blunted by selective KOP-r antago-
nist nor-BNI, providing evidence that there is an involvement of endogenous
dynorphin/KOP-r system in modulation of HPA activity (Allen et al., 2013; Zhou
et al., 2013b).

As shown in this review, there has been substantial progress in understanding how
exposure to drug of abuse interacts with stress-responsive brain systems in order to
regulate addictive behaviors. The endogenous opioid systems (including POMC/
MOP-r and dynorphin/KOP-r systems) clearly play a major role in heroin addiction,
and specific gene alterations may contribute to stress responsivity and may affect
vulnerability to develop heroin addiction and to relapse. Other stress-responsive sys-
tems mentioned above (including the vasopressin with its V1b receptors, orexin with
its receptors, and the HPA axis) are also potentially involved in opiate addiction. By
targeting multiple neurotransmitter pathways, combination medications are likely to
have enhanced efficacy over the traditional single-medication approach. Indeed, the
above-mentioned neurobiological studies have found supporting observations, given
that several stress-responsive systems are profoundly altered by chronic heroin ex-
posure. For example, though naltrexone is an available therapy for alcohol depen-
dence, this and other single-pathway targeted pharmacotherapies (e.g., acamprosate
on NMDA receptors) have only shown modest therapeutic value over placebo, indi-
cating a need for new compounds with greater efficacy (Müller et al., 2014). Perhaps,
given the complexity of the interactions, a potential useful strategy may be to combine
compounds that target different neuropharmacological mechanisms (i.e., naltrexone
+ acamprosate, or methadone + modafinil) (e.g., Heyser et al., 2003).
References 247
REFERENCES
Allen, C.P., Zhou, Y., Leri, F., 2013. Effect of food restriction on cocaine locomotor sensiti-
zation in Sprague–Dawley rats: role of kappa opioid receptors. Psychopharmacology
(Berl) 226, 571–578.
Baimel, C., Bartlett, S.E., Chiou, L.C., Lawrence, A.J., Muschamp, J.W., Patkar, O., Tung, L.W.,
Borgland, S.L., 2015. Orexin/hypocretin role in reward: implications for opioid and other
addictions. Br. J. Pharmacol. 172, 334–348.
Bisagno, V., Cadet, J.L., 2014. Stress, sex, and addiction: potential roles of corticotropin-
releasing factor, oxytocin, and arginine-vasopressin. Behav. Pharmacol. 25, 445–457.
Bodnar, R.J., 2014. Endogenous opiates and behavior: 2013. Peptides 62, 67–136.
Boutrel, B., Cannella, N., de Lecea, L., 2010. The role of hypocretin in driving arousal and
goal-oriented behaviors. Brain Res. 1314, 103–111.
Breese, G.R., Sinha, R., Heilig, M., 2011. Chronic alcohol neuroadaptation and stress contrib-
ute to susceptibility for alcohol craving and relapse. Pharmacol. Ther. 129, 149–171.
Brown, R.M., Lawrence, A.J., 2009. Neurochemistry underlying relapse to opiate seeking be-
havior. Neurochem. Res. 34, 1876–1887.
Calipari, E.S., España, R.A., 2012. Hypocretin/orexin regulation of dopamine signaling:
implications for reward and reinforcement mechanisms. Front. Behav. Neurosci. 6, 54.
Chou, T.C., Lee, C.E., Lu, J., Elmquist, J.K., Hara, J., Willie, J.T., 2001. Orexin (hypocretin)
neurons contain dynorphin. J. Neurosci. 21, RC168.
Colombo, G., Lobina, C., Carai, M.A.M., Gessa, G.L., 2006. Phenotypic characterization of
genetically selected Sardinian alcohol-preferring (sP) and -non preferring (sNP) rats.
Addict. Biol. 11, 324–338.
Cowley, M.A., Smart, J.L., Rubinstein, M., Cerdan, M.G., Diano, S., Horvath, T.L., Cone, R.D.,
Low, M.J., 2001. Leptin activates anorexigenic POMC neurons through a neural network in
the arcuate nucleus. Nature 411, 480–484.
de Lecea, L., Kilduff, T.S., Peyron, C., Gao, X., Foye, P.E., Danielson, P.E., 1998. The hypo-
cretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad.
Sci. U.S.A. 95, 322–327.
Di Chiara, G., 2002. Nucleus accumbens shell and core dopamine: differential role in behavior
and addiction. Behav. Brain Res. 137, 75–114.
D’Souza, M.S., Markou, A., 2010. Neural substrates of psychostimulant withdrawal-induced
anhedonia. Curr. Top. Behav. Neurosci. 3, 119–178.
Edwards, S., Guerrero, M., Ghoneim, O.M., Roberts, E., Koob, G.F., 2012. Evidence that
vasopressin V1b receptors mediate the transition to excessive drinking in ethanol-
dependent rats. Addict. Biol. 17, 76–85.
Georgescu, D., Zachariou, V., Barrot, M., Mieda, M., Willie, J.T., Eisch, A.J., Yanagisawa, M.,
Nestler, E.J., Dileone, R.J., 2003. Involvement of the lateral hypothalamic peptide orexin in
morphine dependence and withdrawal. J. Neurosci. 23, 3106–3111.
Griebel, G., Simiand, J., Serradeil-Le Gal, C., Wagnon, J., Pascal, M., Scatton, B., 2002.
Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin V1b receptor
antagonist, SSR149415, suggest an innovative approach for the treatment of stress-related
disorders. Proc. Natl. Acad. Sci. U.S.A. 99, 6370–6375.
Harris, G.C., Wimmer, M., Aston-Jones, G., 2005. A role for lateral hypothalamic orexin neu-
rons in reward seeking. Nature 437, 556–559.
Heilig, M., Egli, M., Crabbe, J.C., Becker, H.C., 2010. Acute withdrawal, protracted absti-
nence and negative affect in alcoholism: are they linked? Addict. Biol. 15, 169–184.
Heyser, C.J., Moc, K., Koob, G.F., 2003. Effects of naltrexone alone and in combination with
acamprosate on the alcohol deprivation effect in rats. Neuropsychopharmacology
28, 1463–1471.
Houshyar, H., Gomez, F., Manalo, S., Bhargava, A., Dallman, M., 2003. Intermittent
morphine administration induces dependence and is a chronic stressor in rats.
Ignar, D.M., Kuhn, C.M., 1990. Effects of specific mu and kappa opiate tolerance and absti-
nence on hypothalamo-pituitary-adrenal axis secretion in the rat. J. Pharmacol. Exp. Ther.
255, 1287–1295.
Kallupi, M., Cannella, N., Economidou, D., Ubaldi, M., Ruggeri, B., Weiss, F., Massi, M.,
Marugan, J., Heilig, M., Bonnavion, P., de Lecea, L., Ciccocioppo, R., 2010. Neuropeptide
S facilitates cue-induced relapse to cocaine seeking through activation of the hypothalamic
hypocretin system. Proc. Natl. Acad. Sci. U.S.A. 107, 19567–19572.
Kelsey, J.E., Verhaak, A.M., Schierberl, K.C., 2015. The kappa-opioid receptor antagonist,
nor-binaltorphimine (nor-BNI), decreases morphine withdrawal and the consequent con-
ditioned place aversion in rats. Behav. Brain Res. 283, 16–21.
Koob, G., Kreek, M.J., 2007. Stress, dysregulation of drug reward pathways, and the transition
to drug dependence. Am. J. Psychiatry 164, 1149–1159.
Koob, G.F., 2008. A role for brain stress systems in addiction. Neuron 59, 11–34.
Koshimizu, T.A., Nakamura, K., Egashira, N., Hiroyama, M., Nonoguchi, H., Tanoue, A.,
2012. Vasopressin V1a and V1b receptors: from molecules to physiological systems.
Physiol. Rev. 92, 1813–1864.
Le Merrer, J., Becker, J.A., Befort, K., Kieffer, B.L., 2009. Reward processing by the opioid
system in the brain. Physiol. Rev. 89, 1379–1412.
Leri, F., Zhou, Y., Kreek, M.J., Jacklin, D., 2009. Effect of modafinil on stress-induced co-
caine seeking and cocaine cross-sensitization in laboratory rats (Abstract). In: CPDD
71st Annual Meeting (Reno, Sparks), Nevada.
Li, C., Pleil, K.E., Stamatakis, A.M., Busan, S., Vong, L., Lowell, B.B., Stuber, G.D., Kash, T.L.,
2012. Presynaptic inhibition of gamma-aminobutyric acid release in the bed nucleus of the
stria terminalis by kappa opioid receptor signaling. Biol. Psychiatry 71, 725–732.
Maiya, R., Zhou, Y., Norris, E., Kreek, M.J., Strickland, S., 2009. Tissue plasminogen acti-
vator modulates the cellular and behavioral response to cocaine. Proc. Natl. Acad. Sci.
U.S.A. 106, 1983–1988.
Martinez, J.A., Vargas, M.L., Fuente, T., Garcia, J.D.R., Milanes, M.V., 1990. Plasma beta-
endorphin and cortisol levels in morphine-tolerant rats and in naloxone-induced with-
drawal. Eur. J. Pharmacol. 182, 117–123.
Minzenberg, M.J., Carter, C.S., 2008. Modafinil: a review of neurochemical actions and
effects on cognition. Neuropsychopharmacology 33, 1477–1502.
Müller, C.A., Geisel, O., Banas, R., Heinz, A., 2014. Current pharmacological treatment
approaches for alcohol dependence. Expert Opin. Pharmacother. 15, 471–481.
Narita, M., Nagumo, Y., Hashimoto, S., Narita, M., Khotib, J., Miyatake, M., 2006. Direct
involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway
and related behaviors induced by morphine. J. Neurosci. 26, 398–405.
Nealey, K.A., Smith, A.W., Davis, S.M., Smith, D.G., Walker, B.M., 2011. k-Opioid receptors
are implicated in the increased potency of intra-accumbens nalmefene in ethanol-
dependent rats. Neuropharmacology 61, 35–42.
Negus, S.S., Rice, K.C., 2009. Mechanisms of withdrawal-associated increases in heroin self-
administration: pharmacologic modulation of heroin vs food choice in heroin-dependent
rhesus monkeys. Neuropsychopharmacology 34, 899–911.
References 249
Pang, T.Y., Du, X., Catchlove, W.A., Renoir, T., Lawrence, A.J., Hannan, A.J., 2013. Positive
environmental modification of depressive phenotype and abnormal hypothalamic-
pituitary-adrenal axis activity in female C57BL/6J mice during abstinence from chronic
ethanol consumption. Front. Pharmacol. 4, 1–9. Article 93.
Rodd-Henricks, Z.A., McKinzie, D.L., Li, T.K., Murphy, J.M., McBride, W.J., 2002. Cocaine
is self-administered into the shell but not the core of the nucleus accumbens of Wistar rats.
Roper, J.A., O’Carroll, A., Young III, W.S., Lolait, S.J., 2011. The vasopressin AVPr1b
receptor: molecular and pharmacological studies. Stress 14, 98–115.
Rubinstein, M., Mogil, J.S., Japon, M., Chan, E.C., Allen, R.G., Low, M.J., 1996. Absence of
opioid stress-induced analgesia in mice lacking beta-endorphin by site-directed mutagen-
esis. Proc. Natl. Acad. Sci. U.S.A. 93, 3995–4000.
Salome, N., Stemmelin, J., Cohen, C., Griebel, G., 2006. Differential roles of amygdaloid
nuclei in the anxiolytic- and antidepressant-like effects of the V1b receptor antagonist,
SSR149415, in rats. Psychopharmacology (Berl) 187, 237–244.
Schank, J.R., Ryabinin, A.E., Giardino, W.J., Ciccocioppo, R., Heilig, M., 2012. Stress-
related neuropeptides and addictive behaviors: beyond the usual suspects. Neuron
76, 192–208.
Schlosburg, J.E., Whitfield Jr., T.W., Park, P.E., Crawford, E.F., George, O., Vendruscolo, L.F.,
Koob, G.F., 2013. Long-term antagonism of k opioid receptors prevents escalation of and
increased motivation for heroin intake. J. Neurosci. 33, 19384–19392.
Sedki, F., Eigenmann, K., Gelinas, J., Schouela, N., Courchesne, S., Shalev, U., 2015. A role
for kappa-, but not mu-opioid, receptor activation in acute food deprivation-induced rein-
statement of heroin seeking in rats. Addict. Biol. 20, 423–432.
See, R.E., Waters, R.P., 2010. Pharmacologically-induced stress: a cross-species probe for
translational research in drug addiction and relapse. Am. J. Transl. Res. 3, 81–89.
Serradeil-Le Gal, C., Wagnon, J., Simiand, J., Griebel, G., Lacour, C., Guillon, G.,
Barberis, C., Brossard, G., Pascal, M., Soubrie, P., Nisato, D., Pascal, M., Pruss, R.,
Scatton, B., Maffrand, J.P., Le Fur, G., 2002. Characterization of (2S,4R)-1-[5-chloro-1-
[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-
4-hydroxy-N,N-dimethyl-2-pyrrolidine carboxamide (SSR149415), a selective and oral
active vasopressin V1b receptor antagonist. J. Pharmacol. Exp. Ther. 300, 1122–1130.
Shalev, U., Erb, S., Shaham, Y., 2010. Role of CRF and other neuropeptides in stress-induced
reinstatement of drug seeking. Brain Res. 1314, 15–28.
Sharf, R., Sarhan, M., Dileone, R.J., 2010. Role of orexin/hypocretin in dependence and ad-
diction. Brain Res. 1314, 130–138.
Sinha, R., Garcia, M., Paliwal, P., Kreek, M.J., Rounsaville, B.J., 2006. Stress-induced cocaine
craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse
outcomes. Arch. Gen. Psychiatry 63, 324–331.
Sinha, R., Shaham, Y., Heilig, M., 2011. Translational and reverse translational research on the
role of stress in drug craving and relapse. Psychopharmacology (Berl) 218, 69–82.
Smith, R.J., Aston-Jones, G., 2012. Orexin/hypocretin 1 receptor antagonist reduces
heroin self-administration and cue-induced heroin seeking. Eur. J. Neurosci. 35, 798–804.
Spanagel, R., Herz, A., Shippenberg, T.S., 1990. The effects of opioid peptides on dopamine
release in the nucleus accumbens: an in vivo microdialysis study. J. Neurochem.
55, 1734–1740.
Spanagel, R., Herz, A., Bals-Kubik, R., Shippenberg, T.S., 1991. Beta-endorphin-induced
locomotor stimulation and reinforcement are associated with an increase in dopamine
release in the nucleus accumbens. Psychopharmacology (Berl) 104, 51–56.
Spanagel, R., Noori, H.R., Heilig, M., 2014. Stress and alcohol interactions: animal studies and
clinical significance. Trends Neurosci. 37, 219–227.
Sperling, R.E., Gomes, S.M., Sypek, E.I., Carey, A.N., McLaughlin, J.P., 2010. Endogenous
kappa-opioid mediation of stress-induced potentiation of ethanol-conditioned place pref-
erence and self-administration. Psychopharmacology (Berl) 210, 199–209.
Stine, S., Southwick, S., Petrakis, I., Kosten, T., Charney, D., Krystal, J., 2002. Yohimbine-
induced withdrawal and anxiety symptoms in opioid dependent patients. Biol. Psychiatry
51, 642–651.
Vale, W., Spiess, J., Rivier, C., Rivier, J., 1981. Characterization of a 41-residue ovine hypo-
thalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science
213, 1394–1397.
Walker, B.M., Koob, G.F., 2008. Pharmacological evidence for a motivational role of kappa-
opioid systems in ethanol dependence. Neuropsychopharmacology 33, 643–652.
Wigger, A., Sánchez, M.M., Mathys, K.C., Ebner, K., Frank, E., Liu, D., Kresse, A.,
Neumann, I.D., Holsboer, F., Plotsky, P.M., Landgraf, R., 2004. Alterations in central neu-
ropeptide expression, release, and receptor binding in rats bred for high anxiety: critical
role of vasopressin. Neuropsychopharmacology 29, 1–14.
Yeoh, J.W., Campbell, E.J., James, M.H., Graham, B.A., Dayas, C.V., 2014. Orexin antago-
nists for neuropsychiatric disease: progress and potential pitfalls. Front. Neurosci. 8, 36.
Zhou, Y., Spangler, R., Yuferov, V.P., Schlussmann, S.D., Ho, A., Kreek, M.J., 2004. Effects
of selective D1- or D2-like dopamine receptor antagonists with acute “binge” pattern co-
caine on corticotropin-releasing hormone and proopiomelanocortin mRNA levels in the
hypothalamus. Mol. Brain Res. 130, 61–67.
Zhou, Y., Bendor, J.T., Yuferov, V., Schlussman, S.D., Ho, A., Kreek, M.J., 2005. Amygdalar
vasopressin mRNA increases in acute cocaine withdrawal: evidence for opioid receptor
modulation. Neuroscience 134, 1391–1397.
Zhou, Y., Bendor, J., Hofmann, L., Randesi, M., Ho, A., Kreek, M.J., 2006. Mu opioid receptor
and orexin/hypocretin mRNA levels in the lateral hypothalamus and striatum are enhanced
by morphine withdrawal. J. Endocrinol. 191, 137–145.
Zhou, Y., Leri, F., Cummins, E., Hoeschele, M., Kreek, M.J., 2008a. Involvement of arginine
vasopressin and V1b receptor in heroin withdrawal and heroin seeking precipitated by
stress and by heroin. Neuropsychopharmacology 33, 226–236.
Zhou, Y., Cui, C.L., Schlussman, S.D., Choi, J.C., Ho, A., Han, J.S., Kreek, M.J., 2008b.
Effects of cocaine place conditioning, chronic escalating-dose “binge” pattern cocaine
administration and acute withdrawal on orexin/hypocretin and preprodynorphin gene
expressions in lateral hypothalamus of Fischer and Sprague–Dawley rats. Neuroscience
153, 1225–1234.
Zhou, Y., Maiya, R., Norris, E., Kreek, M.J., Strickland, S., 2010. Involvement of tissue plas-
minogen activator in stress responsivity during acute cocaine withdrawal in mice. Stress
13, 481–490.
Zhou, Y., Colombo, G., Carai, M.A., Ho, A., Gessa, G.L., Kreek, M.J., 2011a. Involvement of
arginine vasopressin and V1b receptor in alcohol drinking in Sardinian alcohol-preferring
rats. Alcohol. Clin. Exp. Res. 35, 1876–1883.
Zhou, Y., Litvin, Y., Piras, A.P., Pfaff, D.W., Kreek, M.J., 2011b. Persistent increase in
hypothalamic arginine vasopressin gene expression during protracted withdrawal from
chronic escalating-dose cocaine in rodents. Neuropsychopharmacology 36, 2062–2075.
References 251
Zhou, Y., Colombo, G., Niikura, K., Carai, M.A.M., Femenı́a, T., Garcı́a-Gutiérrez, M.S.,
Manzanares, J., Ho, A., Gessa, G.L., Kreek, M.J., 2013a. Voluntary alcohol drinking
enhances proopiomelanocortin (POMC) gene expression in nucleus accumbens shell
and hypothalamus of Sardinian alcohol-preferring rats. Alcohol. Clin. Exp. Res.
37, E131–E140.
Zhou, Y., Leri, F., Grella, S., Aldrich, J., Kreek, M.J., 2013b. Involvement of dynorphin and
kappa opioid receptor in yohimbine-induced reinstatement of heroin seeking in rats.
Synapse 67, 358–361.
Zhou, Y., Leri, F., Ho, A., Kreek, M.J., 2013c. Suppression of hypothalamic-pituitary-adrenal
axis by acute heroin challenge in rats during acute and chronic withdrawal from chronic
heroin administration. Neurochem. Res. 38, 1850–1860.
Zhou, Y., Leri, F., Cummins, E., Kreek, M.J., 2015. Individual differences in gene expression
of vasopressin, D2 receptor, POMC and orexin: vulnerability to relapse to heroin seeking
in rats. Physiol. Behav. 139, 127–135.
CHAPTER
Opioid neuroscience for

addiction medicine: From
animal models to FDA
approval for alcohol
13
addiction
Wade Berrettini1
Karl E Rickles Professor of Psychiatry, Center for Neurobiology and Behavior, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, PA, USA
1
Abstract
Alcohol addiction is one of the most common and devastating diseases in the world. Given the
tremendous heterogeneity of alcohol-addicted individuals, it is unlikely that one medication
will help nearly all patients. Thus, there is a clear need to develop predictors of response to
existing medications. Naltrexone is a mu opioid receptor antagonist which has been approved
in the United States for treatment of alcohol addiction since 1994. It has limited efficacy, in
part due to noncompliance, but many patients do not respond despite high levels of compli-
ance. There are reports that a mis-sense single-nucleotide polymorphism (rs179919 or A118G)
in the mu opioid receptor gene predicts a favorable response to naltrexone if an individual
carries a “G” allele. This chapter will review the evidence for this hypothesis. The data suggest
that the “G” allele has a complex role in alcohol addiction, increasing the rewarding valence of
alcohol. Whether the G allele increases risk for alcoholism and whether it predisposes to a
beneficial naltrexone response among alcohol-addicted persons must await additional research
with large sample sizes of multiple ethnicities in prospective clinical trials.
Keywords
Opioids, Alcohol addiction, Naltrexone, Pharmacogenetics, mu opioid receptor

253
254 CHAPTER 13 Opioid neuroscience for addiction medicine
1 INTRODUCTION: THE ROLE OF OPIOIDS IN ALCOHOL

REWARD
Ventral tegmental neurons release dopamine at nerve terminals in ventral striatum
and medial prefrontal cortex. Activation of this circuit is a common element of
abused drugs, including alcohol (e.g., Di Chiara and Imperato, 1988; for review
see Koob and Volkow, 2010). Thus, alcohol shares in common with nicotine, co-
caine, amphetamine, morphine, etc., this property of enhancing dopaminergic trans-
mission in ventral striatum and medial prefrontal cortex. Both animal model and
human studies are in agreement on this point (Boileau et al., 2003; Gilman et al.,
2008; Spanagel, 2009). This release of dopamine in the ventral striatum and medial
prefrontal cortex is partially enhanced by stimulation of mu opioid receptors (for
which endorphin is the primary ligand) located on inhibitory GABAergic interneu-
rons in the ventral tegmental area. The GABAergic interneurons inhibit the dopami-
nergic ventral tegmental neurons, whose activation signals reward. Thus, mu opioid
receptor agonists enhance the likelihood of ventral tegmental dopaminergic neuron
activation (and the experience of reward) by lessening the tonic inhibition of the as-
sociated GABAergic interneurons ( Johnson and North, 1992; Spanagel et al., 1992;
Tanda and DiChiara, 1998).
Given this circuitry, it has been consistently shown that endogenous opioids play
a role in ethanol reinforcement in various animal paradigms. Endorphin elevations
after alcohol are seen in discrete reward regions of the hypothalamus (Popp and
Erickson, 1998), ventral tegmentum, and ventral striatum (Rasmussen et al.,
1998). It is important to note that endorphin-deficient rats continue to self-administer
alcohol, indicating that endorphin is not the sole mechanism of alcohol reward
(Grahame et al., 1998). The importance of mu opioid receptor activation as a mech-
anism for alcohol reward is underscored by the fact that alcohol consumption in
alcohol-preferring rats is persistently reduced after inactivating mu opioid receptors
in the ventral striatum (Myers and Robinson, 1999). Similarly, decreased alcohol
self-administration is observed in primates after pretreatment with opioid antagonists
(Altshuler et al., 1980). C57Bl/6J mice, an inbred strain which prefers alcohol, have
increased endorphin release in the hypothalamus after alcohol administration
(De Waele et al., 1992). Alcohol-preferring rats have high levels of opioid gene
mRNA species in the hypothalamus, prefrontal cortex, and mediodorsal nucleus
of the thalamus (Marinelli et al., 2000), as well as increased mu opioid receptor den-
sity in the ventral striatum and medial prefrontal cortex.
2 CLINICAL STUDIES OF NALTREXONE IN ALCOHOLISM

The development of a substantial body of evidence, in the 1980s, that naltrexone (an
orally active mu opioid receptor antagonist) diminished alcohol self-administration
in animal models (Altshuler et al., 1980; Kiianmaa et al., 1983; Myers et al., 1986;
3 A118G OPRM1: Molecular and cellular effects 255
Volpicelli et al., 1986) led to the first use of naltrexone in alcohol-addicted popula-
tions in a controlled clinical trial (Volpicelli et al., 1992), the promising outcome of
which was immediately confirmed in a second controlled clinical trial (O’Malley
et al., 1992). Naltrexone was found to reduce alcohol craving and relapse to heavy
drinking (operationally defined as five or more drinks/day for a man, four or more for
a woman), but did not reduce abstinence rates. On the basis of these two controlled
trials, naltrexone was approved by the FDA, in the absence of the usual pharmaceu-
tical industry interest.
In the intervening 20 years, there have been more than 30 clinical trials of nal-
trexone in alcohol addiction (for review, see Bouza et al., 2004; Pettinati et al., 2006;
Srisurapanont and Jarusuraisin, 2005). While the majority of these clinical trials
demonstrate efficacy of naltrexone in reducing risk for relapse to heavy drinking,
the effect size is small, with many patients having no benefit. This has resulted in
multiple reports in which the naltrexone arm outcomes are not significantly better
than the placebo arm outcomes (e.g., Krystal et al., 2001). This is an expected out-
come, given the tremendous heterogeneity of clinical alcohol addiction. It is likely
that important clinical characteristics, such as compliance, severity and duration of
alcohol addiction, comorbidity (both medical and psychiatric), and/or attendance at
psychosocial treatment, may influence outcomes.
In this situation, multiple investigators have attempted to define clinical charac-
teristics which might enhance the probability of naltrexone response. Some clinical
measures have shown promise in characterizing a naltrexone responder: high alcohol
craving (Chick et al., 2000; Monterosso et al., 2001; O’Malley et al., 2002) and
strong family history of alcohol addiction (Monterosso et al., 2001), but family his-
tory of alcohol addiction did not predict response to naltrexone in the combine mul-
ticenter trial (Capone et al., 2011). Alcohol addicts who experience greater euphoria
after alcohol may have a better response to naltrexone (Volpicelli et al., 1995).
3 A118G OPRM1 MIS-SENSE SINGLE-NUCLEOTIDE

POLYMORPHISM: MOLECULAR AND CELLULAR EFFECTS
A common mis-sense single-nucleotide polymorphism (rs1799971) in the first exon
of the mu opioid receptor gene, OPRM1, was described by Bergen et al. (1997),
A118G, or N40G, reflecting the fact that the A allele encodes asparagine, while
the minor G allele encodes aspartate. The A (asparagine) allele is thought to be
N-glycosylated (Huang et al., 2012), whereas this is not possible for the
G (aspartate) allele, as there is no free amino group. Subsequent study (e.g.,
Crowley et al., 2003; Gelernter et al., 1999; Szeto et al., 2001; Tan et al., 2003)
revealed large ethnic differences in allele frequencies (see Table 1).
This allele has been the subject of multiple molecular investigations to determine
its functional consequences, in terms of gene expression, protein translation, receptor
signaling, and receptor density. Initially, Bond et al. (1998) reported that the minor
“G” allele mu opioid receptor resulted in decreased affinity for binding to
Table 1 Frequency of G Allele for A118G SNP in Ethnic Groups

Ethnic Group Frequency G (%) Ethnic Group Frequency G (%)
African 1 Korean 31
African-American 3 Chinese 35
Swedish 11 Malaysian 43
European-American 15 Indian 47
b c
2.5 Cortical lobes 0.20 Pons section
250 a 300 c
2.0
0.15 200
OPRM1 mRNA level
OPRM1 mRNA level
(OPRM1/b - actin)
(OPRM1/b - actin)
3H-Diprenorphine
binding (fmol/mg)
3H-Diprenorphine
binding (fmol/mg)
200
1.5
150
0.10 *
1.0 100
100
0.05
0.5 50
** **
0.00
0.0 AA AG GG 0 0
AA AG GG A G C T AA AG GG
FIGURE 1
Transcriptional and translational efficiency of the 118G allele is markedly limited, compared
to the A allele. *P<0.05; **P<0.01.
beta-endorphin, compared to the common “A” allele receptor. There was no change
in binding affinity for alkaloid ligands. This result has not been confirmed in subse-
quent investigations (Beyer et al., 2004; Ramchandani et al., 2011). In one such
study, transfected HEK293 cells (a fibroblastoid cell type) were used (Beyer
et al., 2004), but the 118G allele did not differ in binding affinity for beta-endorphin,
compared to 118A. Beyer et al. (2004) also reported that the 118G allele was not
different from the 118A allele in rate of desensitization, internalization, or resensi-
tization, but 118G had decreased transcription, compared to 118A. Ramchandani
et al. (2011) also did not report differences in kinetics of binding of beta-endorphin
to the 118G, compared to 118A. Mahmoud et al. (2011), using a whole-cell patch
clamp technique in acutely dissociated trigeminal ganglion neurons, reported that
morphine was fivefold less active at the “G” allele receptor form in activating a
Ca2+ channel. There was no such difference for fentanyl. Zhang et al. (2005) con-
ducted allelic imbalance studies in postmortem human brain, revealing a marked de-
crease in 118G allele mRNA (see Fig. 1). In a second experiment, they showed
in vitro evidence of a marked decreased translation of the 118G mRNA (see
Fig. 4; Zhang et al., 2005).
4 A118G OPRM1: Animal model studies 257

POLYMORPHISM: ANIMAL MODEL STUDIES
In the murine OPRM1 gene, there is no equivalent of the A118G naturally occurring
variation. A homologous variation (A112G, with the A allele encoding asparagines
and the G allele encoding aspartate, as in the human OPRM1 gene) was created by
bacterial artificial chromosome engineering and murine transgenic techniques by
Mague et al. (2009). They reported decreased transcription and translation of the
G allele in transgenic C57Bl/6 mouse brain (see Fig. 2), a result congruous with
the human postmortem brain ex vivo results of Zhang et al. (2005), as well as the
in vitro results of Beyer et al. (2004). There was a blunted locomotor response to
morphine in the 112G mice, as well as decreased morphine conditioned place pref-
erence (CPP) in 112G female mice, the latter being a sexually dimorphic response,
with 112G males showing the expected CPP response to morphine.
Two other forms of transgenic mice were produced, using homologous recombi-
nation to replace the murine OPRM1 exon 1 with one of the two forms (118A and
118G) of human OPRM1 exon 1 (Ramchandani et al., 2011). These investigators
conducted in vivo microdialysis experiments in the ventral striatum, demonstrating
that the 118G mice had the expected elevations in dopamine release after alcohol,
while the 118A mice had no significant increase over baseline (see Fig. 6). These
data suggest that the “G” allele conveys an increased rewarding valence to alcohol,
compared to the “A” allele (Fig. 3).
A mouse model for A118G

A C57B1/6J BAC was subject to site-directed mutagenesis to
create a A112G variant, homologous to the human A118G. LoxP-
mediated homologous recombination was used with the BAC to
create C57BI/6J with this variant. As with the human post-mortem
brain studies of A118G, the G allele in the mouse brain
reduces transcription and translation.
0.4 1.0 2500
A/A
Specific binding
G/G
MOPR protein
2000
MOPR mRNA
0.3
(dpm)
1500
0.2 0.5
1000
0.1 500
Hypo PAG VTA NAc Ctx Hipp A/A G/G A/A G/G
FIGURE 2
A mouse homologue of the 118G allele also shows decreased transcriptional and translational
efficiency. *P<0.05; **P<0.01; ***P<0.001; †P<0.00001.
Mague et al. (2009).
FIGURE 3
In vivo microdialysis proves that a mouse homologue of the 118G allele confers increased
alcohol-induced dopamine release in the ventral striatum and presumably increased reward.
Ramchandani et al. (2011).
FIGURE 4
The rhesus homologue of the 118G, 77G, is associated with increased alcohol consumption,
which is attenuated by naltrexone treatment.
Barr et al. (2010).
There have been several studies of a similar SNP in the rhesus monkey, the C77G,
which results in a homologous amino acid change, asparagine to aspartate (Barr et al.,
2007, 2010; Vallender et al., 2010). Both groups report that the G allele monkeys con-
sume significantly more alcohol than the CC monkeys. Further, both groups note that
naltrexone significantly decreases alcohol intake in the GG monkeys (Fig. 4).
5 A118G OPRM1: Human pharmacogenetic studies of alcohol 259
However, there is scant evidence that the G allele increases alcohol consumption
in the general population.
These reports, taken together, are consistent with the hypothesis that the 118G
allele (or its equivalent in mouse and primate) conveys a greater rewarding effect
of alcohol, a difference which is inhibited by naltrexone. These studies are remark-
ably consistent, given the species, paradigm, technical, and molecular engineering
differences among these studies.

POLYMORPHISM: HUMAN PHARMACOGENETIC STUDIES
OF ALCOHOL
There have been several pharmacogenetic reports of the A118G SNP in human lab-
oratory experiments involving alcohol (Ramchandani et al., 2011; Ray and
Hutchison, 2004, 2007; Ray et al., 2010; Setiawan et al., 2011). In a laboratory in-
vestigation of the A118G pharmacogenetics of alcohol reward, Ray and Hutchison
(2004, 2007) demonstrated that the G allele carriers experienced significantly greater
euphoria after standard oral doses of alcohol (while controlling for breath alcohol
concentration), compared to AA persons. Further, naltrexone significantly blunted
the euphoria in the G allele carriers and was without effect in the AA group
(see Fig. 5).
In agreement with this result, Ramchandani reported that G allele carriers had a
greater striatal release of dopamine after alcohol (using a raclopride PET scan
FIGURE 5
118G allele carriers have a greater euphoria response to alcohol, compared to
homozygous A persons; naltrexone blunts the alcohol-induced euphoria for 118G carriers,
but has no such effect in persons who are homozygous A.
FIGURE 6
Raclopride positron emission tomograph (PET) scans reveal that 118G carriers have increase
ventral striatum alcohol-induced dopamine release, compared to persons who are
homozygous A.
Ramchandani et al. (2011).
technique), compared to AA participants (see Fig. 6). In a more naturalistic approach,

Ray et al. (2010) studied drinking habits of social drinkers over a 5-day period, an-
alyzing subjective responses to alcohol by A118G genotype. G allele carriers
reported more significantly more “vigor” less negative mood after drinking, com-
pared to the AA group. Similarly, Setiawan et al. (2011) studied the subjective re-
sponse to alcohol in social drinkers after a dose of naltrexone. Naltrexone
significantly decreased the ethanol-induced “euphoria” to a priming dose of alcohol
in subjects with the G allele, compared to AA participants.
Ashenhurst et al. (2012) found evidence for a OPRD1 SNP (rs4654327) influenc-
ing the response to naltrexone in the presence of alcohol, such that carriers of the
A allele at this locus reported greater naltrexone-induced blunting of alcohol stimula-
tion and alcohol craving compared to GG homozygotes. Further, TT homozygotes
reported lower naltrexone-influenced alcohol sedation as compared to carriers of
the C allele at the OPRK1 SNP, rs997917. These studies indicate that multiple opioid
receptors may influence the response of individuals to alcohol in the presence of nal-
trexone. The genetic complexity of the naltrexone–alcohol interaction is further illus-
trated by a human lab study of alcohol-dependent subjects, in which there was a
statistically significant increased stimulation and positive mood among OPRM1
G allele carriers who were dopamine transporter (DAT) VNTR 10–10 homozygotes,
compared with other genotype groups (Ray et al., 2014). Lastly, in a neuroimaging
study of alcohol-dependent individuals, Schacht et al. (2013) reported a three-way
interaction between medication and A118G and DAT VNTR genotypes on ventral
striatum alcohol-induced activation, such that, among G allele carriers, DAT 10–10
homozygotes had less activation after naltrexone than 9-repeat-allele carriers.
6 Pharmacogenetic studies 261
Taken together, these human laboratory studies of the A118G variant on effect of
alcohol are remarkably consistent, with the clear conclusion that the G allele permits
people to experience alcohol in a more rewarding manner, compared to AA individ-
uals. It is also notable that naltrexone is able to blunt this euphoria in G allele carriers,
but not in AA persons. This latter observation is consistent with subjective reports of
the effect of naltrexone in clinical trials for alcohol addiction, in which the medica-
tion attenuated alcohol-induced euphoria among responders (Volpicelli et al., 1995).
6 PHARMACOGENETIC STUDIES OF NALTREXONE CLINICAL

TRIALS FOR ALCOHOL ADDICTION
There have been multiple pharmacogenetic studies of naltrexone clinical trials for
alcohol addiction published in the last decade. The first such publication (Oslin
et al., 2003) was a retrospective analysis of three naltrexone trials of similar design,
two conducted at the University of Pennsylvania and one at the University of
Connecticut. Compliance was monitored by riboflavin testing and by pill counts.
Eighty-two patients (71 of European descent) who were randomized to naltrexone
and 59 randomized to placebo (all of European descent) in one of three randomized
placebo-controlled clinical trials of naltrexone were genotyped at the A+118G
(Asn40Asp) and C+17T (Ala6Val) SNPs in the mu opioid gene (OPRM1). The asso-
ciation between genotype and drinking outcomes was measured over 12 weeks of
treatment. For purposes of examining the pharmacogenetics of naltrexone response,
the analysis was limited to those subjects with well-defined outcome data who had at
minimum 6 weeks exposure to the medication. The primary drinking outcome con-
sidered was relapse to heavy drinking (5 drinks in a single day for men or 4 drinks
for women). This definition of heavy drinking was the primary outcome for each of
the trials. The timeline follow-back method was employed (along with self-report) to
measure alcohol consumption (Sobell and Sobell, 1992). There was a significantly
greater proportion of naltrexone-treated subjects with the G allele variant who did
not return to heavy drinking (no relapse) compared to those with those homozygous
for the A allele (Wald ¼ 4.04, 1 df, OR ¼ 3.47 (95% CI: 1.03–11.67), and p ¼ 0.045;
see Table 2).
Table 2 A118G Genotype and Good Outcome in Naltrexone Studies of

Pharmacotherapy for Alcohol Addiction
Oslin et al. (2003) Anton et al. (2008)
Genotype at Naltrexone Placebo Naltrexone Placebo

A118G (%) (%) (%) (%)
G allele carriers 85a 55 89b 54

Homozygous A 56 46 56 50
a
p ¼ 0.04, odds ratio ¼ 3.5.
b
p ¼ 0.005, genotype medication interaction; odds ratio ¼ 5.8.
This finding was confirmed in a larger multisite study of naltrexone, acampro-

sate, and placebo for alcohol addiction (Anton et al., 2008). Alcohol-addicted sub-
jects were treated for 16 weeks with 100 mg of naltrexone. All participants received
medical management alone or with combined behavioral intervention.
When considering only those patients receiving medical management alone,
there was an significant effect of naltrexone on “good outcome” among the 118G
carriers, while there was no such effect for the patients receiving naltrexone who
were homozygous A118 (see Table 2). However, there was no such effect in the nal-
trexone group receiving medical management with combined behavioral interven-
tion. The combined behavioral intervention was delivered by licensed behavioral
health specialists in up to 20 flexible participant need–adjusted 50-min sessions.
Combined behavioral intervention, an intensive and specific alcohol intervention,
may have compensated for the placebo effect, thereby suppressing the chances of
observing a main effect of naltrexone or a genetic interaction. The data presented
by Anton et al. (2008) are consistent with this thinking. A gene medication interac-
tion may be observable only in patients who can show obvious benefit from the med-
ication over placebo.
In a small Korean study of naltrexone in alcohol addiction (Kim et al., 2009),
subjects adherent to naltrexone treatment with one or two copies of the Asp40 allele
took a significantly longer time than the Asn40 group to relapse to heavy drinking
(p ¼ 0.014). Although not significant, the Asn40 group treated with naltrexone had a
10.6 times greater relapse rate than the Asp40 variant group. There was no effect on
abstinence.
In the Veterans Administration multisite study of naltrexone in alcohol addiction,
Gelernter et al. (2007) reported that the 118G allele did not predict outcome among
149 participants in the naltrexone group and 64 in the placebo group. There are sev-
eral possible explanations for this result. First, the efficacy of naltrexone is certainly
influenced by compliance, and the compliant population was defined as those who
opened the medication bottle a minimum of 50% of the time, so that medication com-
pliance was defined liberally. Second, it is likely that high levels of comorbidity in-
fluence response to naltrexone. The study population had substantial rates of
recurrent unipolar illness, antisocial personality, and anxiety disorders and had se-
vere alcohol addiction of long duration. These factors might overwhelm any genetic
predisposition to respond to naltrexone. Third, the study had limited power: for ex-
ample, there were only nine 118G carriers in the placebo group.
Coller et al. (2011) recently reported the results of a naltrexone and cognitive be-
havioral therapy trial in 100 Australian alcohol-addicted persons. They reported an
overall effect of naltrexone on relapse to heavy drinking, but no influence of the
A188G variants. The absence of a control group makes this study less ideal, as does
the small sample size, with 68 study completers.
Taken together, the A118G clinical trials in naltrexone treatment for alcohol ad-
diction remain promising, but there are clear unanswered question, including the in-
fluence of counseling, compliance, and comorbidity on outcome. Available depot
formulations of naltrexone may reduce noncompliance, but the influence of
References 263
comorbidity and counseling may be more difficult to resolve. It will be necessary to

conduct pharmacogenetic alcohol addiction naltrexone trials, for which participants
are randomized by A118G genotype into the naltrexone or placebo arm to reduce
possible sources of bias. These trials should be characterized by:
(1) large size (at least 100 persons per arm, including oversampling of G allele
carriers) to ensure adequate power;
(2) rigorous assessment of compliance;
(3) randomization stratified by genotype;
(4) careful assessment of comorbidity;
(5) modest psychotherapeutic intervention, so as to mirror “real world” clinical
practice.
Only one such study has been published which has these characteristics (Oslin et al.,
2015), and there was no influence of the G allele on outcome among those random-
ized to naltrexone.

There are extensive data, across species, to suggest that the 118G form of the mu
opioid receptor is characterized by decreased transcription and translation. There
are convincing data, from murine, primate, and human laboratory studies, that the
118G (or its species-specific homologue) variant permits alcohol to have a greater
rewarding valence, leading to increased alcohol consumption. Further, the human
and rhesus data are equally convincing that naltrexone is able to blunt this greater
rewarding signal. Lastly, the possibility that A118G alleles can be used clinically
to identify alcohol-addicted persons with a greater probability to have a beneficial
response to naltrexone is a hypothesis that deserves testing on a large scale, with
the characteristics noted above.
REFERENCES
Altshuler, H.L., Phillips, P.A., Feinhandler, D.A., 1980. Alteration of ethanol self-
administration by naltrexone. Life Sci. 26, 679–688.
Anton, R., Oroszi, G., O’Malley, S., Couper, D., Swift, R., Pettinati, H., Goldman, D., 2008.
m opioid receptor Asn40Asp predicts naltrexone response. Arch. Gen. Psychiatry 65 (11),
135–144.
Ashenhurst, J.R., Bujarski, S., Ray, L.A., 2012. Delta and kappa opioid receptor polymor-
phisms influence the effects of naltrexone on subjective responses to alcohol. Pharmacol.
Barr, C.S., Schwandt, M., Lindell, S.G., Chen, S.A., Goldman, D., Suomi, S.J., Higley, J.D.,
Heilig, M., 2007. Association of a functional polymorphism in the mu-opioid receptor
gene with alcohol response and consumption in male rhesus macaques. Arch. Gen. Psy-
chiatry 64, 369–376.
Barr, C.S., Chen, S.A., Schwandt, M.L., Lindell, S.G., Sun, H., Suomi, S.J., Heilig, M., 2010.
Suppression of alcohol preference by naltrexone in the rhesus macaque: a critical role of
genetic variation at the mu-opioid receptor gene locus. Biol. Psychiatry 67, 78–80.
Bergen, A.W., Kokoszka, J., Peterson, R., et al., 1997. Mu opioid receptor gene variants: lack
of association with alcohol dependence. Mol. Psychiatry 2 (6), 490–494.
Beyer, A., Koch, T., Schröder, H., Schulz, S., Höllt, V., 2004. Effect of the A118G polymor-
phism on binding affinity, potency and agonist-mediated endocytosis, desensitization, and
resensitization of the human mu-opioid receptor. J. Neurochem. 89, 553–560.
Boileau, I., et al., 2003. Alcohol promotes dopamine release in the human nucleus accumbens.
Synapse 49, 226–231.
Bond, C., LaForge, K.S., Tian, M., Melia, D., Zhang, S., Borg, L., Gong, J., Schluger, J.,
Strong, J.A., Leal, S.M., Tischfield, J.A., Kreek, M.J., Yu, L., et al., 1998. Single-
nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin
binding and activity: possible implications for opiate addiction. Proc. Natl. Acad. Sci.
U.S.A. 95 (16), 9608–9613.
Bouza, C., Angeles, M., Muñoz, A., Amate, J.M., 2004. Efficacy and safety of naltrexone and
acamprosate in the treatment of alcohol dependence: a systematic review. Addiction
99, 811–828.
Capone, C., Kahler, C.W., Swift, R.M., O’Malley, S.S., 2011. Does family history of
alcoholism moderate naltrexone’s effects on alcohol use? J. Stud. Alcohol Drugs
72, 135–140.
Chick, J., Anton, R., Checinski, K., Croop, R., Drummond, D.C., Farmer, R., Labriola, D.,
Marshall, J., Moncrieff, J., Morgan, M.Y., Peters, T., Ritson, B., 2000. A multicenter
double-blind randomized trial of naltrexone in the treatment of alcohol dependence or
abuse. Alcohol Alcohol. 35, 587–593.
Coller, J.K., Cahill, S., Edmonds, C., Farquharson, A.L., Longo, M., Minniti, R., Sullivan, T.,
Somogyi, A.A., Whilte, J.M., 2011. OPRM1 A118G genotype fails to predict the effec-
tiveness of naltrexone treatment for alcohol dependence. Pharmacogenet. Genomics
21, 902–905.
Crowley, J.J., Oslin, D.W., Patkar, A.A., Gottheil, E., DeMaria Jr., P.A., O’Brien, C.P.,
Berrettini, W.H., Grice, D.E., 2003. A genetic association study of the mu opioid receptor
and severe opioid dependence. Psychiatr. Genet. 13, 169–173.
De Waele, J.P., Papachristou, D.N., Gianoulakis, C., 1992. The alcohol-preferring C57BL/6
mice present an enhanced sensitivity of the hypothalamic beta-endorphin system to eth-
anol than the alcohol-avoiding DBA/2 mice. J. Pharmacol. Exp. Ther. 261 (2), 788–794.
Di Chiara, G., Imperato, A., 1988. Drugs abused by humans preferentially increase synaptic
dopamine concentrations in the mesolimbic system of freely moving rats. Proc. Natl.
Acad. Sci. U.S.A. 85, 5274–5278.
Gelernter, J., Kranzler, H., Cubells, J., 1999. Genetics of two m opioid receptor gene (OPRM1)
exon I polymorphisms: population studies, and allele frequencies in alcohol- and drug-
dependent subjects. Mol. Psychiatry 4, 476–483.
Gelernter, J., Gueorguieva, R., Kranzler, H.R., et al., 2007. Opioid receptor gene (OPRM1,
OPRK1, and OPRD1) variants and response to naltrexone treatment for alcohol depen-
dence: results from the VA Cooperative Study. Alcohol. Clin. Exp. Res. 31 (4), 555–563.
Gilman, J.M., Ramchandani, V.A., Davis, M.B., Bjork, J.M., Hommer, D.W., 2008. Why we
like to drink: a functional magnetic resonance imaging study of the rewarding and anxi-
olytic effects of alcohol. J. Neurosci. 28, 4583–4591.
References 265
Grahame, N.J., Low, M.J., Cunningham, C.L., 1998. Intravenous self-administration of eth-
anol in beta-endorphin-deficient mice. Alcohol. Clin. Exp. Res. 22 (5), 1093–1098.
Huang, P., Chen, C., Mague, S.D., Blendy, J.A., Liu-Chen, L.Y., 2012. A common single nu-
cleotide polymorphism A118G of the mu opioid receptor alters its N-glycosylation and
protein stability. Biochem. J. 441, 379–386.
Johnson, S.W., North, R.A., 1992. Opioids excite dopamine neurons by hyperpolarization of
local interneurons. J. Neurosci. 12, 483–488.
Kiianmaa, K., Hoffman, P.L., Tabakoff, B., 1983. Antagonism of the behavioral effects of eth-
anol by naltrexone in BALB/c, C57BL/6, and DBA/2 mice. Psychopharmacology (Berl.)
79, 291–294.
Kim, S.G., Kim, C.M., Choi, S.W., Jae, Y.M., Lee, H.G., Son, B.K., Kim, J.G., Choi, Y.S.,
Kim, H.O., Kim, S.Y., Oslin, D.W., 2009. A micro opioid receptor gene polymorphism
(A118G) and naltrexone treatment response in adherent Korean alcohol-dependent pa-
tients. Psychopharmacology (Berl) 201, 611–618.
Koob, G.F., Volkow, N.D., 2010. Neurocircuitry of addiction. Neuropsychopharmacology
35, 217–238.
Krystal, J.H., Cramer, J.A., Krol, W.F., Kirk, G.F., Rosenheck, R.A., 2001. Naltrexone in the
treatment of alcohol dependence. N. Engl. J. Med. 345, 1734–1739.
Mague, S.D., Isiegas, C., Huang, P., Liu-Chen, L.Y., Lerman, C., Blendy, J.A., 2009. Mouse
model of OPRM1 (A118G) polymorphism has sex-specific effects on drug-mediated be-
havior. Proc. Natl. Acad. Sci. U.S.A. 106, 10847–10852.
Mahmoud, S., Thorsell, A., Sommer, W.H., Heilig, M., Holgate, J.K., Bartlett, S.E.,
Ruiz-Velasco, V., 2011. Pharmacological consequence of the A118G μ opioid receptor
polymorphism on morphine- and fentanyl-mediated modulation of Ca2+ channels in
humanized mouse sensory neurons. Anesthesiology 115, 1054–1062.
Marinelli, P.W., Kiianmaa, K., Gianoulakis, C., 2000. Opioid propeptide mRNA content and
receptor density in the brains of AA and ANA rats. Life Sci. 66 (20), 1915–1927.
Monterosso, J.R., Flannery, B.A., Pettinati, H.M., et al., 2001. Predicting treatment response to
naltrexone: the influence of craving and family history. Am. J. Addict. 10 (3), 258–268.
Myers, R.D., Robinson, D.E., 1999. Mu and D2 receptor antisense oligonucleotides injected in
nucleus accumbens suppress high alcohol intake in genetic drinking HEP rats. Alcohol
18 (2–3), 225–233.
Myers, R.D., Borg, S., Mossberg, R., 1986. Antagonism by naltrexone of voluntary alcohol
selection in the chronically drinking macaque monkey. Alcohol 3, 383–388.
O’Malley, S.S., Jaffe, A.J., Chang, G., Schottenfeld, R.S., Meyer, R.E., Rounsaville, B., 1992.
Naltrexone and coping skills therapy for alcohol dependence: a controlled study. Arch.
Gen. Psychiatry 49, 881–887.
O’Malley, S.S., Krishnan-Sarin, S., Farren, C., Sinha, R., Kreek, M.J., 2002. Naltrexone
decreases craving and alcohol self-administration in alcohol-dependent subjects and
activates the hypothalamo-pituitary-adrenocortical axis. Psychopharmacology (Berl.)
160, 19–29.
Oslin, D., Berrettini, W.H., Kranzler, H.R., Pettinati, H., Gelernter, J., Volpicelli, J.R.,
O’Brien, C.P., 2003. A functional polymorphism in the mu opioid receptor gene is asso-
ciated with therapeutic response in alcohol-dependent patients treated with naltrexone.
Neuropsychopharmacol 28, 1546–1552.
Oslin, D.W., Leong, S.H., Lynch, K.G., Berrettini, W.H., O’Brien, C.P., Gordon, A.J.,
Rustalis, M., 2015. A randomized clinical trial of naltrexone versus placebo for the
treatment of alcohol dependence: investigating the pharmacogenetics of the mu-opioid re-

ceptor gene polymorphism, rs1799971. JAMA Psychiatry 72, 430–437.
Pettinati, H.M., O’Brien, C.P., Rabinowitz, A.R., Wortman, S.P., Oslin, D.W., Kampman, K.M.,
Dackis, C.A., 2006. The status of naltrexone in the treatment of alcohol dependence: specific
effects on heavy drinking. J. Clin. Psychopharmacol. 26, 610–625.
Popp, R.L., Erickson, C.K., 1998. The effect of an acute ethanol exposure on the rat brain
POMC opiopeptide system. Alcohol 16 (2), 139–148.
Ramchandani, V.A., Umhau, J., Pavon, F.J., Ruiz-Valasco, V., Margas, W., Sun, H.,
Damadzic, R., Eskay, R., Schoor, M., Thorsell, A., Schwandt, M.L., Sommer, W.H.,
George, D.T., Parsons, L.H., Herscovitch, P., Hommer, D., Heilig, M., 2011. A genetic
determinant of the striatal dopamine response to alcohol in men. Mol. Psychiatry
16, 809–817.
Rasmussen, D.D., Bryant, C.A., Boldt, B.M., Colasurdo, E.A., Levin, N., Wilkinson, C.W.,
1998. Acute alcohol effects on opiomelanocortinergic regulation. Alcohol. Clin. Exp.
Res. 22 (4), 789–801.
Ray, L.A., Hutchison, K.E., 2004. A polymorphism of the mu-opioid receptor gene (OPRM1)
and sensitivity to the effects of alcohol in humans. Alcohol. Clin. Exp. Res. 28 (12),
1789–1795.
Ray, L.A., Hutchison, K.E., 2007. Effects of naltrexone on alcohol sensitivity and genetic
moderators of medication response: a double-blind placebo-controlled study. Arch.
Gen. Psychiatry 64 (9), 1069–1077.
Ray, L.A., Miranda Jr., R., Tidey, J.W., McGeary, J.E., MacKillop, J., Gwaltney, C.J.,
Rohsenow, D.J., Swift, R.M., Monti, P.M., 2010. Polymorphisms of the mu-opioid recep-
tor and dopamine D4 receptor genes and subjective responses to alcohol in the natural en-
vironment. J. Abnorm. Psychol. 119, 115–125.
Ray, L.A., Bujarski, S., Squeglia, L.M., Ashenhurst, J.R., Anton, R.F., 2014. Interactive ef-
fects of OPRM1 and DAT1 genetic variation on subjective responses to alcohol. Alcohol
Alcohol. 49, 261–270.
Schacht, J.P., Anton, R.F., Voronin, K.E., Randall, P.K., Li, X., Henderson, S., Myrick, H.,
2013. Interacting effects of naltrexone and OPRM1 and DAT1 variation on the neural re-
sponse to alcohol cues. Neuropsychopharmacology 38, 414–422.
Setiawan, E., Pihl, R.O., Cox, S.M., Gianoulakis, C., Palmour, R.M., Benkelfat, C.,
Leyton, M., 2011. The effect of naltrexone on alcohol’s stimulant properties and self-
administration behavior in social drinkers: influence of gender and genotype. Alcohol.
Clin. Exp. Res. 35, 1134–1141.
Sobell, L.C., Sobell, M.B., 1992. Timeline follow-back: a technique for assessing self-reported
alcohol consumption. In: Litten, R., Allen, J. (Eds.), Measuring Alcohol Consumption.
Humana Press Inc, Totowa, NJ, pp. 41–65.
Spanagel, R., 2009. Alcoholism: a systems approach from molecular physiology to addictive
behavior. Physiol. Rev. 89, 649–705.
Spanagel, R., Herz, A., Shippenberg, T.S., 1992. Opposing tonically active endogenous opioid
systems modulate the mesolimbic dopaminergic pathway. Proc. Natl. Acad. Sci. U.S.A.
89, 2046–2050.
Srisurapanont, M., Jarusuraisin, N., 2005. Naltrexone for the treatment of alcoholism: a meta-
analysis of randomized controlled trials. Int. J. Neuropsychopharmacol. 8, 267–280.
Szeto, C.Y., Tang, N.L., Lee, D.T., Stadlin, A., 2001. Association between mu opioid receptor
gene polymorphisms and Chinese heroin addicts. Neuroreport 12, 1103–1106.
Tan, E.C., Tan, C.H., Karupathivan, U., Yap, E.P., 2003. Mu opioid receptor gene polymor-
phisms and heroin dependence in Asian populations. Neuroreport 14, 569–572.
References 267
Tanda, G.L., Di Chiara, G., 1998. A dopamine mu(1) opioid link in the rat ventral tegmentum
shared by palatable food (Fonzies) and non-psychostimulant drugs of abuse. Eur. J. Neu-
rosci. 10, 1179–1187.
Vallender, E.J., Ruedi-Bettschen, D., Miller, G.M., Platt, D.M., 2010. A pharmacogenetic
model of naltrexone-induced attenuation of alcohol consumption in rhesus monkeys. Drug
Alcohol Depend. 109, 252–256.
Volpicelli, J.R., Davis, M.A., Olgin, J.E., 1986. Naltrexone blocks the post-shock increase of
ethanol consumption. Life Sci. 38, 841–847.
Volpicelli, J.R., Alterman, A.I., Hayashida, M., O’Brien, C.P., 1992. Naltrexone in the treat-
ment of alcohol dependence. Arch. Gen. Psychiatry 49, 876–880.
Volpicelli, J.R., Watson, N.T., King, A.C., Sherman, C.E., O’Brien, C.P., 1995. Effect of nal-
trexone on alcohol “high” in alcoholics. Am. J. Psychiatry 152 (4), 613–615.
Zhang, Y., Wang, D.X., Johnson, A.D., Papp, A.C., Sadee, W., 2005. Allelic expression im-
balance of human mu opioid receptor (OPRM1) caused by variant A118G. J. Biol. Chem.
280, 32618–32624.
CHAPTER
Competing neurobehavioral
decision systems theory of
cocaine addiction: From
mechanisms to therapeutic
14
opportunities
Warren K. Bickel*,1, Sarah E. Snider*, Amanda J. Quisenberry*, Jeffrey S. Stein*,
Colleen A. Hanlon†
*Addiction Recovery Research Center, Virginia Tech Carilion Research Institute, Roanoke,
VA, USA
†
Medical University of South Carolina, Charleston, SC, USA
1
Corresponding author: Tel.: +1-540-526-2088, Fax: 540-985-3361,
Abstract
Cocaine dependence is a difficult-to-treat, chronically relapsing disorder. Multiple scientific
disciplines provide distinct perspectives on this disorder; however, connections between dis-
ciplines are rare. The competing neurobehavioral decision systems (CNDS) theory posits that
choice results from the interaction between two decision systems (impulsive and executive)
and that regulatory imbalance between systems can induce pathology, including addiction.
Using this view, we integrate a diverse set of observations on cocaine dependence, including
bias for immediacy, neural activity and structure, developmental time course, behavioral
comorbidities, and the relationship between cocaine dependence and socioeconomic status.
From the CNDS perspective, we discuss established and emerging behavioral, pharmacolog-
ical, and neurological treatments and identify possible targets for future treatments. The ability
of the CNDS theory to integrate diverse findings highlights its utility for understanding co-
caine dependence and supports that dysregulation between the decision systems contributes
to addiction.
Keywords
Cocaine dependence, Competing neurobehavioral decision systems, Impulsivity, Self-control,
Executive function, Delay discounting, Dual systems, Transcranial magnetic stimulation

269
270 CHAPTER 14 CNDS theory of cocaine addiction
1 INTRODUCTION
Cocaine is a powerful psychoactive and addictive substance. Approximately 15% of
cocaine users develop dependence within the first decade after initial use, with life-
time incidence of dependence estimated at 20% (Lopez-Quintero et al., 2011;
Wagner and Anthony, 2002). In some racial minorities, these estimates are even
higher (e.g., 35% lifetime incidence of dependence in African American users)
(Lopez-Quintero et al., 2011). Cocaine dependence is difficult to treat and is recog-
nized as a chronically relapsing disorder, in which affected individuals choose con-
tinued drug use despite negative consequences, and return to use after periods of
abstinence. Understanding the processes that undergird these choices is an important
undertaking for the science and treatment of this disorder.
A variety of scientific approaches have tried to understand and explain cocaine
dependence. Some have focused on molecular variables, such as pharmacological
action (Volkow et al., 1999); others have focused on demographics, including
age, race, and socioeconomic status (SES) (Lopez-Quintero et al., 2011; Palamar
et al., 2015). These multiple levels of analysis provide distinct perspectives on co-
caine dependence, but connections across levels have been rare. A thorough under-
standing of these multilevel phenomena, in our view, will require a scientific theory
or paradigm that not only can integrate observations across levels in a compelling
way, but can also suggest novel hypotheses. As Henri Poincaré noted in his classic
text, Science and Hypothesis (Poincaré, 1905), “Science is built up of facts, as a
house is built of stones; but an accumulation of facts is no more a science than a heap
of stones is a house (p. 157).”
The question we should ask is what would we want from such a theory that could
set the extant facts in order? At the very least, any such theory should integrate the
neuroscience of cocaine’s effects on the brain, developmental processes associated
with drug use initiation, the relationship of SES to cocaine use, and the high prev-
alence of certain comorbidities. Such a theory should also have the capacity to sug-
gest novel treatments and perhaps reveal mechanisms underlying established
treatments.
We have been involved with formulating a view, referred to as the competing
neurobehavioral decision systems (CNDS) theory (Bickel and Yi, 2008; Bickel
et al., 2007, 2012a) that has considerable integrative power. This view, consistent
with a broad array of dual-systems theories, suggests that choices result from the
interaction between the two decision systems and that those who are experiencing
addiction suffer from imbalance or dysregulation between these two systems.
In this chapter, we will examine cocaine dependence from the perspective of this
theory. To accomplish this, we will first give a brief synopsis of this theoretical
view and examine the evidence to support the dysregulation between the dual sys-
tems in individuals with cocaine dependence. Next, we will examine how this per-
spective provides insight on the relationship between cocaine dependence and
developmental life course, SES, and comorbidities. Finally, we will examine the
2 The competing neurobehavioral decision systems theory 271
implications of the CNDS perspective for existing and emerging approaches to

the treatment of cocaine dependence.
2 THE COMPETING NEUROBEHAVIORAL DECISION SYSTEMS

THEORY
Dual-systems models of decision-making have been discussed since Descartes and
have evolved to many variations and applications (Sanfey and Chang, 2008), partic-
ularly in the areas of self-control (Metcalfe and Mischel, 1999) and addiction
(Bechara, 2005; Goldstein and Volkow, 2002, 2011; Jentsch and Taylor, 1999). In
decision-making research, most models refer to the dual systems as System 1 and
System 2. System 1 refers to unconscious and automatic processes, requiring little
effort, while System 2 refers to conscious, controlled, and effortful processes
(Evans, 2008; Evans and Stanovich, 2013).
The CNDS theory is a dual-systems model that accounts for self-control failure
(Bickel et al., 2007, 2011a), has been directly applied to addiction (Bickel et al.,
2011a; Sofis et al., 2014) and emphasizes the relative control between impulsive
and executive decision systems. The impulsive system, comprised of the limbic
and paralimbic brain regions, and executive system, comprised of the prefrontal
and parietal cortices, are interdependent and compete for relative control during
decision-making (see Bickel et al., 2012a for pictorial representations). Normal func-
tioning results when the systems are in regulatory balance; however, when the two
systems are not in regulatory balance, pathology may result (Bickel et al., 2015).
Although worthwhile, systematic comparison of the CNDS theory and other dual-
systems models is beyond the scope of this chapter, thus we reserve such compari-
sons for future discussions.
Importantly, delay discounting is a behavioral measure of self-control that des-
ignates the relative strength of the competing decision systems (Bickel et al., 2012b;
McClure and Bickel, 2014). Delay discounting procedures measure future valuation
by asking participants if they would prefer a smaller, immediate amount of a com-
modity or a larger, delayed amount. The immediate amount is titrated until a point of
subjective equality (the indifference point) is determined. A hyperbolic function of-
ten best accounts for the fit of the indifference points across delays and is represented
by the equation (Mazur, 1987),
V ¼ A=ð1 + kDÞ;
where V is the subjective value of the reinforcer, A is the amount of the reinforcer, D
is the delay to receipt of the reinforcer, and k is a free parameter that serves as an
index of discounting (higher values of k indicate higher rates of discounting). Nic-
otine- (Bickel et al., 1999), alcohol- (Petry, 2001), cocaine- (Bickel et al., 2011b,
2014a; Heil et al., 2006), and heroin-dependent (Madden et al., 1997) individuals
discount future rewards more than controls. Higher rates of discounting, then, reflect
hyperactive control by the impulsive decision system, consistent with the bias for
immediate reward evident in addiction (Bickel et al., 2011a).
The study of neuroeconomics, which combines psychology, economics, and neu-
roscience (Bickel et al., 2011a), has provided confirmatory neural evidence for the
actions of the CNDS (described in the following sections). When participants com-
plete delay-discounting procedures in an MRI scanner, relative activity between the
executive and impulsive systems varies, dependent upon the choice being made. For
example, choices for the immediate and delayed reinforcer result in greater activity
in the impulsive and executive systems, respectively (McClure et al., 2004, 2007).
Moreover, when the reinforcer is delayed for both choices, the limbic system shows
no differential activation. Thus, activation of the impulsive decision system depends
on the presence of an immediate reinforcer (McClure et al., 2004).
2.1 THE IMPULSIVE DECISION SYSTEM

The impulsive decision system, comparable to System 1, is embodied in the limbic
(e.g., midbrain, amygdala, habenular commissure, and striatum) and paralimbic
(e.g., insula and nucleus accumbens) brain regions (Bickel et al., 2007). Habit for-
mation, emotional responding, and the acquisition of primary reinforcers to satisfy
biological needs (Bickel et al., 2013) are controlled by the impulsive decision
system.
As discussed above, imaging studies have confirmed that the impulsive decision
system is involved in the choice for immediate reinforcers in delay discounting.
Choice for immediate reinforcers (McClure et al., 2004) selectively activate the para-
limbic cortex and parts of the limbic system, including ventral striatum, medial orbi-
tofrontal cortex, medial prefrontal cortex, posterior cingulate cortex, and left
posterior hippocampus (McClure et al., 2004, 2007).
2.2 THE EXECUTIVE DECISION SYSTEM

The second decision system of the CNDS, comparable to System 2, is embodied in
the parietal lobes and portions of the prefrontal cortex, including the dorsolateral pre-
frontal cortex (Bickel et al., 2007). Some overlap of function in the decisions systems
exists for several areas of the prefrontal cortex, including the orbitofrontal cortex.
The cortical pathways of the executive decision system are responsible for planning,
memory, attention, and future valuation (Bickel et al., 2013). Neuroeconomic evi-
dence has demonstrated activation of the lateral prefrontal cortex and parietal lobe
during decision-making in delay discounting for monetary and primary reinforcers
(i.e., juice) regardless of delay, indicating the executive system is involved in all de-
cisions (McClure et al., 2004, 2007). Moreover, greater activation in the executive
system structures occurs during the more difficult choices requiring greater execu-
tive function.
2 The competing neurobehavioral decision systems theory 273
2.3 THE COMPETING NEUROBEHAVIORAL DECISION SYSTEMS

THEORY IN HEALTH AND ADDICTION
When regulatory balance is achieved between the impulsive and executive decision
systems, an individual is considered self-controlled and is likely to have no
dysfunction (Bickel et al., 2015). Conversely, hyperactive control by either the im-
pulsive or executive decision system can lead to pathological behavior. Many com-
binations of relative strength of each system are possible (Bickel et al., 2013).
Consider Fig. 1 that shows a continuum from low to high control by the impulsive
decision system on the y-axis and on the x-axis, low to high executive control. The
diagonal line represents regulatory balance between the two decision systems.
Shaded regions represent high risk for engaging in negative health behaviors.
The pathological decision-making strategies associated with these behaviors
emerge when control by the impulsive decision system overpowers control by
the executive decision system. For example, high impulsive system control coupled
with low or medium executive control results in greater relative control by the
impulsive decision system and can result in pathological decision-making (e.g.,
bias toward smaller, immediate over larger, delayed consequences) (Bickel
et al., 2011a, 2013).
Imbalance of the CNDS is evident in many disease states where individuals
have bias for immediate consequences over delayed, healthier choices. Hyper-
active control of the impulsive decision system results in patterns of behavior con-
sistent with obesity, legal and illicit substance use, and gambling problems.
Regulatory imbalance can also be a result of hyperactive control by the executive
system.
FIGURE 1
The relative control of the impulsive and executive decision systems, represented graphically.
The diagonal line represents regulatory balance between the systems. The shaded
regions indicate an imbalance between the two systems producing a bias for immediate
over delayed rewards.
3 THE COMPETING NEUROBEHAVIORAL DECISIONS SYSTEMS

THEORY AND COCAINE
3.1 NEURAL EVIDENCE OF THE IMBALANCE OF DECISION SYSTEMS
Imbalance of the CNDS contributes to excessive discounting and addiction behav-
iors (Bickel et al., 2012b). Addiction occurs when the executive system is weak and
the hyperactive impulsive decision system drives choice (Bechara, 2005). Cocaine
use, via neuronal plasticity, promotes a transition in regulation from the prefrontal
cortices to the striatum leading to compulsive and habitual drug seeking (Everitt
et al., 2008). Advances in imaging have provided us with tools to examine the neural
evidence of this imbalance in cocaine addiction.
3.1.1 Hyperactivation of the impulsive system

The impulsive decision system is comprised of regions of the limbic system and re-
lated areas (McClure et al., 2004). One of these regions, the orbitofrontal cortex, is
associated with: (1) the reinforcing aspects of cocaine, (2) immediate choice prefer-
ences, and (3) craving and cocaine salience (Lucantonio et al., 2012; McClure et al.,
2004; Steinberg, 2007). Compared to healthy controls, cocaine addicts show in-
creased activation in limbic regions (i.e., the amygdala, anterior cingulate cortex,
and striatum) following exposure to cocaine cues (Childress et al., 1999; Garavan
et al., 2000). These increases in activation suggest regions responsible for drug crav-
ing and hyperactivation in craving states. Hyperactivation of the impulsive system in
cocaine users is also consistent with findings of acute withdrawal circuits becoming
hypermetabolic during spontaneous craving (Kalivas and Volkow, 2005; Lucantonio
et al., 2012). Moreover, hyperactivation of the medial orbitofrontal cortex and ante-
rior cingulate cortex (structures with impulsive functions) occurs following acute
methylphenidate administration in cocaine addicts (Wilcox et al., 2011), suggestive
of system over-activation following repeated stimulant administration (akin to sen-
sitization observed in animals) (Robinson and Berridge, 1993).
Interestingly, while hyperactivation and hypermetabolism of the limbic system
occurs under certain conditions, cocaine-dependent participants show an overall re-
duction in aspects of the impulsive decision system compared to healthy controls.
These reductions include decreased activation of the orbitofrontal cortex and cingu-
late gyrus (Volkow et al., 1993) and decreased gray matter volume of the amygdala
(Makris et al., 2004) and the ventromedial, orbitofrontal, anterior cingulate, and ante-
roventral insular cortices (Franklin et al., 2002). Although these findings may seem
counterintuitive from the viewpoint of CNDS (i.e., reduced function and structure of
the impulsive decision system in cocaine addicts), cocaine may prime the limbic re-
gions associated with cue salience and motivation, consistent with hyperactivation of
the impulsive decision system following drug administration and contributes to in-
creased craving and compulsive intake (Volkow et al., 2005). Consistently, acute
methylphenidate administration may normalize limbic activation by working simi-
larly to cocaine but with slower pharmacokinetics. That is, in cocaine addicts, acute
3 The competing neurobehavioral decisions systems theory and cocaine 275
methylphenidate increases activation in the anterior cingulate cortex during a cue-

reactivity task (Goldstein et al., 2010), restores response levels to normal after fa-
tigue in a Stroop task (Moeller et al., 2012), and increases resting-state functional
connectivity in limbic regions, including the anterior cingulate cortex (Konova
et al., 2013). Thus, hyperactivation of the impulsive decision system, as a conse-
quence of cocaine priming the system, weakens relative control of the executive sys-
tem and decreases self-control (Noel et al., 2013).
3.1.2 Hypoactivation of the executive system

In addition to hyperactivity of the impulsive system, drugs of abuse cause an inter-
ruption of the top-down processes required for self-control (Dalley et al., 2011). Neu-
ral evidence suggests that cocaine induces executive dysfunction. Although
hyperactivation may occur in some instances, as mentioned above, overall reductions
in signaling, glucose metabolism (Kalivas and Volkow, 2005), and structural volume
(Franklin et al., 2002) in both the impulsive and executive systems are observed after
cocaine use. Moreover, the degree of cocaine use is associated with both structural
and functional deficits in the executive system (Beveridge et al., 2008).
3.2 DEVELOPMENTAL PROCESSES AND COCAINE ADDICTION

3.2.1 Differential development
Evidence of differential development between the CNDS explains impaired self-
control in adolescents, as the two decision systems appear to differentially mature.
During the first half of adolescence (i.e., ages 10–15), dopaminergic activity in-
creases dramatically in brain areas associated with the impulsive decision system
(Sisk and Zehr, 2005), including a dramatic dopamine and dendritic synaptic over-
expression in the striatum (Andersen et al., 2000). Related to this overexpression, the
nucleus accumbens, an area of the impulsive decision system responsible for the re-
warding properties of stimuli, and orbitofrontal cortex display hyperactivation in
children and adolescents compared to adults in resting state (Galvan et al., 2006)
and when completing a monetary reward task (Ernst et al., 2005). Moreover, differ-
ential myelination between limbic and nonlimbic regions enhances activation in the
impulsive decision system (Galvan et al., 2006). As adolescents mature, the overex-
pression and hyperactivation of the impulsive system begins to prune to model an
inverted U-shaped function over time (Sisk and Zehr, 2005; Teicher et al., 1995).
That is, after the overexpression peaks, extra connectivity begins to decline while
the slower to mature executive decision system continues to develop.
Development of the executive decision system includes increases in parietal gray
matter volume (Sisk and Zehr, 2005) along with dramatic dopamine and dendritic
synaptic overexpression in the prefrontal cortex (Andersen et al., 2000). Gray matter
density development and myelination in the frontal and parietal cortices continues
into adulthood (Sowell et al., 2003), thus increasing relative control of the executive
over the impulsive decision systems with age.
3.2.2 Related behaviors

The differential development of the two systems and inverted U-shaped curve of im-
pulsive decision system development is evident in self-control. Paralleling the over-
expression of dopamine and activation of the impulsive decision system, a drastic
increase in risky behavior is present in adolescence. Specifically, self-reported
sensation-seeking and risky sexual behavior increases drastically, peaks in early ad-
olescence, and declines as self-regulatory behavior begins to mature (Baams et al.,
2015; Steinberg, 2007; Steinberg et al., 2008).
Importantly, a longitudinal study modeled the imbalance of the CNDS and
reported that high rates of delay discounting and poor working memory (both mea-
sures of weak executive control) predicted greater subsequent initiation of drug use
(i.e., alcohol, marijuana, and tobacco) (Khurana et al., 2015). Using data from two
large national surveys (Substance Abuse and Mental Health Services
Administration, 2004, 2013), Fig. 2 highlights this increased vulnerability in adoles-
cents by illustrating the percentage of adolescents who used cocaine in the last
30 days by age group. Note, the percentage of use rapidly peaks in adolescence
and declines with increasing age.
3.3 SOCIOECONOMIC STATUS AND COCAINE ADDICTION

A widely demonstrated negative linear relationship exists between SES and illicit
drug use, health problems, and mortality. This monotonic gradient, describing the
relationship between SES and health status, extends from the lowest to the highest
ends of the socioeconomic spectrum. As a result, this relationship cannot be entirely
accounted for by poverty-induced deprivation or healthcare access (Adler and
Stewart, 2010). This gradient represents the health disparity in prevalence of
Percent using cocaine in past 30 days
100
2003
3 2013
0
45 44
50 49
55 54
60 59
4
+
12
13
14
15
16
17
18
19
20
21
22
23
24
26 25
30 29
35 34
40 39
–6
65
–
–
–
–
–
–
–
Age group
FIGURE 2
Percentage of cocaine use in the past month, by age group. The results from the 2003 and
2013 National Survey on Drug Use and Health Surveys are presented. Percentage of use
increases with age, which then slowly dissipates over time.
3 The competing neurobehavioral decisions systems theory and cocaine 277
negative health behaviors (e.g., drug use, risky sexual behavior, and obesity) such
that a lower prevalence of disease states is observed in high-SES individuals and
a higher prevalence is observed in lower SES individuals. The greater the income
inequality within a society, the larger the health disparity (Banks et al., 2006). This
trend is apparent within the United States and is representative of the general trend
showing larger health disparities in countries with more income inequality
(Wilkinson and Pickett, 2011). Rates of mental illness, obesity, and substance use
are disease states strongly associated with SES inequalities (Pampel et al., 2010).
One measure included in SES, education level, contributes to the prevalence of
past year cocaine use and exemplifies this general trend in health disparities. In 2012,
2.4% of people who did not graduate from high school, while only 1.1% of college
graduates, used cocaine in the past year. This relationship between SES and cocaine
use began in the 1990s when risk perception of using cocaine increased and therefore
became less culturally acceptable. As a result, high-SES individuals were more likely
to discontinue cocaine use while low SES individuals continued use (Miech, 2008).
The increased prevalence of cocaine use among lower income individuals demon-
strates the negative socioeconomic gradient present across a wide variety of negative
health behaviors, including cigarette smoking (Hiscock et al., 2012), illicit drug use
(Buka, 2002), and obesity (Baum and Ruhm, 2009).
The CNDS theory can be used as a conceptual framework to explain the discrep-
ancy between the prevalence of negative health behaviors among individuals with
varying SES (Bickel et al., 2014b). The experiences associated with low SES, includ-
ing increased allostatic load and lack of resources (Haushofer and Fehr, 2014; Mani
et al., 2013), disrupt the development and regulatory balance between the impulsive
and executive decision systems (Bickel et al., 2014b; Noble et al., 2012). Exposure to
these environmental circumstances facilitates a biased decision-making process fa-
voring immediate over delayed, healthier consequences. This executive dysfunction
results from hyperactivation of the impulsive decision system and results in contin-
ued choice for immediate rewards, which perpetuates the disparity in negative health
behaviors, including cocaine use.
3.4 COMORBIDITIES WITH OTHER SUBSTANCE USE AND RISKY

SEXUAL BEHAVIOR
The CNDS theory also provides a framework for understanding the relationship be-
tween comorbid disease states and cocaine use. Regulatory imbalance of the systems
resulting from hyperactivity of the impulsive decision system may explain the pres-
ence of decision-making favoring immediate rewards (e.g., cocaine use and risky
sexual behavior) (Chesson et al., 2006; Johnson and Bruner, 2012) over delayed,
more healthy consequences. These decision-making processes are central to many
disease states, which contributes to the incidence of comorbidity (Bickel and
Mueller, 2009). Comorbid substance use, including tobacco (Budney et al., 1993;
Burling et al., 1996), alcohol (Bierut et al., 2008), marijuana (Narvaez et al.,
2014), and opiate use (Bierut et al., 2008), is common in cocaine users although
few treatments intended for cocaine dependence take these comorbidities into ac-
count (Yoon et al., 2013).
4 THE CNDS AND COCAINE TREATMENT

The CNDS theory has been used previously to understand and categorize the effects
of various delay-discounting manipulations (Koffarnus et al., 2013). Here, we apply
a similar analysis to current and emerging treatments for cocaine dependence.
4.1 CONVENTIONAL TREATMENT FOR COCAINE DEPENDENCE

A number of therapies have been successfully used to treat cocaine dependence,
among which cognitive behavioral therapy (CBT) has the largest evidence base
(Carroll and Onken, 2005; Carroll et al., 2008; Maude-Griffin et al., 1998). However,
behavioral measures of executive dysfunction (e.g., poor Stroop performance) con-
sistently predict poor response to these treatments (Aharonovich et al., 2006;
Bleiberg et al., 1994; Moeller et al., 2001; Simpson et al., 1999; Streeter et al.,
2008; Worhunsky et al., 2013; Xu et al., 2010). Likewise, functional and structural
neuroimaging data, such as diminished prefrontal cortex activation and white matter
integrity, further implicate executive dysfunction in poor treatment response (Brewer
et al., 2008; Moeller et al., 2005; Worhunsky et al., 2013; Xu et al., 2010).
Many of these conventional treatments, including CBT, require a complex rep-
ertoire of executive skills (e.g., coping strategies or the ability to recognize dynamic
relapse cues and modify behavior accordingly), which are likely compromised in in-
dividuals demonstrating regulatory imbalance between decision systems. From the
viewpoint of the CNDS, a more promising approach would be to precisely target
areas of dysfunction to produce more uniformly efficacious treatment outcomes
compared to conventional treatment strategies (Bickel et al., 2012b). In the sections
that follow, we consider a number of treatments that may accomplish this goal.
4.2 TREATMENTS TO DECREASE CONTROL OF THE IMPULSIVE

DECISION SYSTEM
4.2.1 Contingency management
One of the most reliable treatments for cocaine and other substance dependence in
recent decades has been contingency management, a behavioral approach that ar-
ranges immediate delivery of monetary or other tangible reinforcers contingent on
physiologically verified drug abstinence (Higgins et al., 1991, 1994) (for review
and meta-analysis, see Lussier et al., 2006; Prendergast et al., 2006). This approach
rapidly reduces cocaine use (Robles et al., 2000) and maintains abstinence over long
periods of time (Poling et al., 2006; Rawson et al., 2002), even in the absence of con-
tinued treatment (Epstein et al., 2003; Higgins et al., 1995; Petry and Martin, 2002).
Moreover, contingency management for cocaine use may be implemented
4 The CNDS and cocaine treatment 279
successfully at relatively low cost (Petry and Martin, 2002; Petry et al., 2004) and
may be paired with adjunctive therapies (e.g., CBT) (Epstein et al., 2003) to further
improve treatment outcomes.
As discussed previously, substance use may be viewed as an intertemporal choice
between immediate drug reinforcement and the temporally diffuse and distant out-
comes associated with drug abstinence (e.g., sustained physical and mental health
and attainment of occupational goals). Regulatory imbalance between decision sys-
tems may predispose individuals toward cocaine use by disproportionately weighting
the value of immediate drug reinforcement. With this in mind, the provision of ex-
trinsic, relatively immediate reinforcement for abstinence in contingency manage-
ment therapies may supplant the naturalistic, delayed outcomes of abstinence
(e.g., improved health and social function) that are otherwise insufficient to impact
behavior in those suffering from regulatory imbalance. In addition, cessation of co-
caine use during contingency management likely facilitates initial contact with these
naturalistic outcomes, perhaps contributing to continued abstinence following treat-
ment (Epstein et al., 2003; Higgins et al., 1995; Petry and Martin, 2002). Consistent
with these mechanisms, a recent study examining contingency management for opi-
oid abuse allowed participants to either redeem these earnings immediately at each
laboratory visit or accumulate their earnings in an account over the course of the
study (Bickel et al., 2010). Participants with the highest baseline rates of delay dis-
counting more frequently redeemed their earnings immediately than participants
with lower rates of delay discounting, demonstrating the selective importance of im-
mediate outcomes for participants with regulatory imbalance. Future studies should
be designed to determine whether a similar finding would be observed with contin-
gency management for cocaine dependence.
4.2.2 Medications
Currently no approved medication exists for stimulant addiction (Brackins et al.,
2011) and replacement therapies with stimulants for cocaine and methamphetamine
addiction have produced equivocal results (Moeller et al., 2008). However, the pos-
sibility remains that replacement agonist therapy may be a viable avenue to decrease
or buffer the hyperactivation of the impulsive decision system during or to prevent
crave states.
For example, dexamphetamine and methylphenidate are long-acting stimulants,
with similar mechanisms of action to cocaine (i.e., increases in extracellular dopa-
mine) and have shown positive results in reducing behaviors related to cocaine ad-
diction. In intravenous cocaine users, dexamphetamine reduced positive urine
samples for cocaine, self-reported use, craving, and criminal activity (Shearer
et al., 2003). Dexamphetamine maintenance also reduces choice preferences for im-
mediate cocaine over money (Rush et al., 2009). Likewise, methylphenidate reduces
reaction to cocaine cues and attenuates anterior cingulate cortex activation in
cocaine-dependent individuals (see review Mariani and Levin, 2012) without impair-
ing inhibitory control in a go/no-go task (Vansickel et al., 2008), offering a stimulant
agonist medication without over activating the impulsive decision system.
Moreover, replacement therapies such as methylphenidate, dexamphetamine, and

atomoxetine are pharmacologically safe for maintenance therapy (Grabowski
et al., 1997; Rush et al., 2009; Stoops et al., 2008). Thus, the benefit of longer acting
agonist medications for use as partial agonist therapies offers a potential avenue to
buffer hyperactivation of the impulsive decision system in cocaine-dependent
individuals.
4.2.3 Neurotherapeutic stimulation

Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation tool
which enables us to selectively activate or inhibit populations of neurons by altering
the frequency and placement of cortical stimulation. When stimulation is delivered
repetitively, at frequencies known to induce long-term potentiation (LTP) or depres-
sion (LTD) of cortical activity, this technique is known as repetitive TMS (rTMS)
(Fitzgerald et al., 2006; Hoogendam et al., 2010; Thickbroom, 2007; Ziemann
et al., 2008). LTP of both behavioral and neural activity is possible by applying either
a single high frequency (e.g., 10 Hz) or an intermittent theta burst frequency to the
cortex. In contrast, transient LTD of behavioral and neural activity is possible by ap-
plying either a single low-frequency (e.g., 1 Hz) or continuous theta burst frequency
to the cortex. rTMS is an FDA-approved treatment for depression and is the only
noninvasive brain stimulation tool available for humans.
A growing body of substance dependence literature suggests that we may be able
to directly dampen limbic circuitry or amplify executive control circuitry in
substance-dependent individuals through rTMS. Consequently, rTMS has garnered
significant attention as an innovative tool for treating substance dependence from
both the National Institutes of Health and in the literature (Barr et al., 2011;
Bellamoli et al., 2014; Gorelick et al., 2014; Wing et al., 2013). In context with
the CNDS, several strategies could be used to develop treatments for substance de-
pendence, including altering the relative control of the impulsive and executive de-
cision systems.
The vulnerability to drug-related cues in treatment-seeking cocaine users is likely
sustained by high functional activity in the impulsive decision system (Ersche et al.,
2012; Moeller et al., 2010; Moreno-Lopez et al., 2012). Consequently, application of
low-frequency TMS, for example, applying LTD-like stimulation to the limbic sys-
tem may reduce sensitivity to cocaine and other substance cues. Given that the nu-
cleus accumbens is one of the primary brain regions involved in craving (Robinson
and Berridge, 1993) and the medial prefrontal cortex is that structure’s primary cor-
tical input, targeting the medial prefrontal cortex would be a method to modulate
nucleus accumbens activity among substance-dependent populations. Recent work
by Cho et al. (2015) demonstrated that LTP-like rTMS (i.e., 10 Hz) to the medial
prefrontal cortex in a group of healthy, nondrug-using individuals was associated
with a significant decrease in dopamine binding potential in the dorsal striatum,
reflecting a release of dopamine in these areas. Although they did not find a signif-
icant change in dopamine binding in the nucleus accumbens, LTP-like stimulation of
the medial prefrontal–striatal circuit increased delay discounting (a behavioral
4 The CNDS and cocaine treatment 281
marker of executive dysfunction). This finding suggests that an LTD-like rTMS

strategy over the medial prefrontal cortex would attenuate activity in this neural cir-
cuit and may reduce drug craving and impulsive decision system control. Prior data
from our laboratory demonstrate that in cocaine users, continuous theta burst stim-
ulation to the frontal lobe selectively decreases activation in the medial prefrontal
cortex and nucleus accumbens (Hanlon et al., 2015). Given that craving for cocaine
is associated with an increase in striatal dopamine, decreasing the sensitivity of this
circuit through rTMS may be a valuable treatment strategy. Future research is re-
quired to determine whether stimulating this location is tolerable in substance-
dependent populations because medial prefrontal cortex stimulation has not been
widely pursued and is subjectively more painful than dorsolateral prefrontal
cortex rTMS.
4.3 TREATMENTS TO INCREASE CONTROL OF THE EXECUTIVE

DECISION SYSTEM
4.3.1 Neurocognitive training
Executive function deficits in chronic cocaine users are well established (Bolla et al.,
2000). Specifically, compared to healthy controls, cocaine-dependent individuals
demonstrate significant impairments of multiple measures of attention, visual and
spatial memory, language and sensory perception functions (Jovanovski et al.,
2005). This executive dysfunction is related to retention rates for relapse prevention
therapy in cocaine users (Aharonovich et al., 2003, 2006). Because functional and
regional overlap exists between executive function areas, including those involved
in making delay-discounting decisions for the delayed reinforcer (Bickel et al.,
2011c; Wesley and Bickel, 2014), training specific executive functions, such as
working memory, may increase executive decision system control leading to pro-
gram retention and a rebalance of the CNDS.
4.3.1.1 Working memory training

Of the impaired executive systems in cocaine addicts, working memory is an exec-
utive function mediated by the prefrontal cortex and is involved in goal-directed be-
havior (Miller and Cohen, 2001). Interestingly, following working memory training,
healthy participants demonstrate increases in prefrontal and parietal region activa-
tion (Olesen et al., 2004). Consistent with the CNDS theory, more activation in these
areas indicate increases in executive decision system functionality and is important
because greater frontoparietal activity occurs when participants choose larger
delayed rewards (McClure et al., 2004). In fact, we have demonstrated decreased de-
lay discounting of monetary rewards following working memory training in cocaine
addicts (Bickel et al., 2011c), thus providing support for this potential approach to
increase executive system functionality. In addition to working memory training, a
second potential treatment, episodic future thinking, shows beneficial executive neu-
rocognitive improvement capabilities.
4.3.1.2 Episodic future thinking

Episodic future thinking is a form of prospection which involves mental simulation
of future events (Atance and O’Neill, 2001). Neural evidence demonstrates that fu-
ture thinking tasks activate frontal cortices (Okuda et al., 2003) associated with the
executive decision system. Moreover, goal-directed simulations activate the prefron-
tal cortex and associated regions (Gerlach et al., 2011). Behaviorally, episodic future
thinking decreases delay discounting, which is predicted by anterior cingulate cortex
activation (Daniel et al., 2013; Peters and Buchel, 2010). Thus, given that poor per-
formance of future thinking is associated with poor executive function (de Vito et al.,
2012), repetition of either working memory training or episodic future thinking may
increase control of the executive decision system, improve valuation of future re-
wards, and provide a valuable adjunct to cocaine cessation therapy.
4.3.2 Medications
Modafinil acts on several neurotransmitter systems including glutamate, GABA, and
dopamine. Similar to the previously proposed agonist therapies to decrease control of
the impulsive decision system, modafinil produces a similar mechanism of action to
cocaine (i.e., increases in dopamine) and produces protracted mild stimulant prop-
erties to promote wakefulness. Modafinil reduces activity in the ventral tegmental
area, an impulsive decision system brain region, and reduces self-reported craving
in response to cocaine cues (Goudriaan et al., 2013), indicative of an attenuation
of craving. Though modafinil has been investigated as an agonist replacement ther-
apy (i.e., to buffer hyperactivation of the impulsive decision system) with mixed re-
sults (Dackis et al., 2012; Hart et al., 2008), modafinil’s actions may be most
beneficial by activating the executive decision system. Modafinil promotes en-
hanced activation of the frontoparietal regions and reduced activation of the ventro-
medial prefrontal cortex (Schmaal et al., 2014), both regions associated with the
valuation of rewards. Behaviorally, modafinil increases several measures of working
memory and attention in cocaine users (Kalechstein et al., 2013). Modafinil reduces
delay discounting in alcohol-dependent participants compared to controls (Schmaal
et al., 2014), and importantly, modafinil does not impair inhibitory control in a go/
no-go task in cocaine-dependent individuals (Vansickel et al., 2008) offering another
stimulant medication that increases executive function without overactivating the
impulsive system.
Modafinil, alongside other medications, has been classified as a nootropic, or a
cognitive enhancer. Nootropics are reported to increase working and visual memory,
decision-making, and planning (Turner et al., 2004), indicating that pharmacological
interventions can improve executive decision system function and regulatory bal-
ance of the CNDS. Interestingly, improving deficits in neurotransmitter systems with
nicotine agonists, norepinephrine transporter inhibitors, or alpha-2 adrenergic ago-
nists, coincide with some improved attention, response inhibition, and working
memory (Sofuoglu, 2010). Evidence that these other systems modulate executive
function warrants further investigation into nootropics enhancing the executive de-
cision system to improve treatment outcomes. Moreover, the benefits of
pharmacological treatments can provide a valuable adjunct therapy to behavioral in-

terventions such as contingency management or working memory training, allowing
for synergistic treatment.
4.3.3 Neurotherapeutic stimulation

Vulnerability to drug-related cues may be due to low functional activity in the ex-
ecutive decision system of substance-dependent individuals (Goldstein et al.,
2004; Kubler et al., 2005; Moeller et al., 2010) suggesting that an LTP-like rTMS
stimulation of the executive decision system (e.g., dorsolateral prefrontal cortex)
might enable better resistance against drug cues. To date, the vast majority of rTMS
studies in addiction have targeted the dorsolateral prefrontal cortex (Amiaz et al.,
2009; Camprodon et al., 2007; Eichhammer et al., 2003; Herremans et al., 2012,
2013; Hoppner et al., 2011; Li et al., 2013; Mishra et al., 2010; Politi et al., 2008;
Pripfl et al., 2014). While many of these studies demonstrated that LTP-like rTMS
stimulation to the dorsolateral prefrontal cortex can result in a significant reduction
of craving, the neurobiological mechanism is unclear. For example, in a comprehen-
sive review on the efficacy of rTMS for smoking cessation, Wing et al. (2013)
reported beneficial effects on tobacco craving following LTP-like rTMS on the dor-
solateral prefrontal cortex.
Neurotherapeutic stimulation is a developing area of research for treatment of
drug dependence. Future research needs to resolve two questions, which cortical lo-
cation should be targeted in order to maximally affect the circuitry associated with
regulatory balance between decision systems and what stimulation frequency should
be used. Identification of a single “optimal” protocol for all individuals or all drug
classes is not likely. For example, some individuals may benefit the most from a
treatment strategy that amplifies the executive decision system (e.g., 10 Hz dorsolat-
eral prefrontal cortex stimulation) while others may benefit most from a strategy that
attenuates the impulsive decision system (e.g., 1 Hz medial prefrontal stimulation).
Before moving forward with expensive and slow multisite clinical trials investigat-
ing the efficacy of rTMS as a viable treatment tool for addiction, exploration of these
combinations of frequencies and cortical targets to maximize potential impact should
be considered. TMS may provide a powerful new tool to use as an adjunct to behav-
ioral and pharmacotherapeutic addiction treatment. Given that no FDA-approved
pharmacotherapy for cocaine dependence exists, brain stimulation may be a partic-
ularly useful therapeutic technique.

Integration of findings from multiple scientific disciplines and levels of analysis into
a robust conceptual system will permit and suggest experiments, and perhaps lead to
novel treatments for cocaine dependence. Scientific paradigms in the field of addic-
tion have continuously evolved and have had at least four major paradigm shifts in
the last hundred years (Bickel et al., 2013). The CNDS theory constitutes the most
recent paradigm shift and is a valuable perspective for addiction research in two
ways. First, it stipulates that a fundamental contributor to the addiction process is
a dysregulation between the impulsive and executive decision systems. Second, it
identifies those two decision systems as targets for interventions.
In this chapter, we have shown that numerous observations could be integrated
when viewed from the perspective of the CNDS. Armed with that view, we connect
observations regarding the immediacy bias evident in addiction, neural activity and
structure, the developmental pattern associated with cocaine and other drug use vul-
nerabilities, the SES gradient of cocaine and other drug dependencies, and the pres-
ence of comorbidities. Such integration supports use of the CNDS theory to guide
treatment strategies.
For treatment of cocaine dependence, our view is that treatments or interventions
should be supported by a theoretical conceptualization. If the conceptualization of a
disorder changes, that change should force a reevaluation of the treatment efficacy.
The CNDS is a relatively new conceptualization and permits understanding of the
efficacy of existing treatments (e.g., CBT), but also suggests novel approaches
(e.g., rTMS) to either decrease activity in the impulsive decision system or increase
activity in the executive decision system. Efficacy of these novel approaches will, in
part, continue to test the CNDS and indicate the range of its relevance.
The CNDS, like many paradigmatic approaches, is an approximation of a more
complete paradigm. The examination and use of the CNDS in the treatment of co-
caine and other drug dependence disorders are not based on the ultimate value of the
theory, but rather its proximal utility in making new discoveries and assisting those
trapped by cocaine dependence. Whether the CNDS continues to provide new re-
search insights that contribute to treatment or will instead give way to an even more
robust perspective will await subsequent investigation. In either case, the continued
exploration and elaboration of this integrated view contributes to the science of ad-
diction, in general, and cocaine dependence in particular.
ACKNOWLEDGMENTS
The following grants contributed to the support of the authors during the development of this
work: NIH grants U19CA157345, R01DA034755, R01AA021529, and R01DA036617.
REFERENCES
Adler, N.E., Stewart, J., 2010. Health disparities across the lifespan: meaning, methods, and
mechanisms. Ann. N. Y. Acad. Sci. 1186, 5–23.
Aharonovich, E., Nunes, E., Hasin, D., 2003. Cognitive impairment, retention and abstinence
among cocaine abusers in cognitive-behavioral treatment. Drug Alcohol Depend. 71 (2),
207–211.
References 285
Aharonovich, E., Hasin, D.S., Brooks, A.C., Liu, X., Bisaga, A., Nunes, E.V., 2006. Cognitive
deficits predict low treatment retention in cocaine dependent patients. Drug Alcohol De-
pend. 81 (3), 313–322.
Amiaz, R., Levy, D., Vainiger, D., Grunhaus, L., Zangen, A., 2009. Repeated high-frequency
transcranial magnetic stimulation over the dorsolateral prefrontal cortex reduces cigarette
craving and consumption. Addiction 104 (4), 653–660.
Andersen, S.L., Thompson, A.T., Rutstein, M., Hostetter, J.C., Teicher, M.H., 2000. Dopa-
mine receptor pruning in prefrontal cortex during the periadolescent period in rats.
Synapse 37 (2), 167–169.
Atance, C.M., O’Neill, D.K., 2001. Episodic future thinking. Trends Cogn. Sci. 5 (12), 533.
Baams, L., Dubas, J.S., Overbeek, G., van Aken, M.A.G., 2015. Transitions in body and be-
havior: a meta-analytic study on the relationship between pubertal development and ad-
olescent sexual behavior. J. Adolesc. Health 56 (6), 586–598.
Banks, J., Marmot, M., Oldfield, Z., Smith, J.P., 2006. Disease and disadvantage in the United
States and in England. JAMA 295 (17), 2037–2045.
Barr, M.S., Farzan, F., Wing, V.C., George, T.P., Fitzgerald, P.B., Daskalakis, Z.J., 2011. Re-
petitive transcranial magnetic stimulation and drug addiction. Int. Rev. Psychiatry 23 (5),
454–466.
Baum II, C.L., Ruhm, C.J., 2009. Age, socioeconomic status and obesity growth. J. Health
Econ. 28 (3), 635–648.
neurocognitive perspective. Nat. Neurosci. 8 (11), 1458–1463.
Bellamoli, E., Manganotti, P., Schwartz, R.P., Rimondo, C., Gomma, M., Serpelloni, G., 2014.
rTMS in the treatment of drug addiction: an update about human studies. Behav. Neurol.
2014, 815215.
Beveridge, T.J., Gill, K.E., Hanlon, C.A., Porrino, L.J., 2008. Parallel studies of cocaine-
related neural and cognitive impairment in humans and monkeys. Philos. Trans. R.
Soc. Lond. Ser. B Biol. Sci. 363 (1507), 3257–3266.
Bickel, W.K., Mueller, E.T., 2009. Toward the study of trans-disease processes: a novel ap-
proach with special reference to the study of co-morbidity. J. Dual Diagn. 5 (2), 131–138.
Bickel, W.K., Yi, R., 2008. Temporal discounting as a measure of executive function: Insights
from the competing neuro-behavioral decision system hypothesis of addiction. In:
Houser, D., McCabe, K. (Eds.), Neuroeconomics: Advances in Health Services Research.
Vol. 20. Emerald Group Publishing, Bingley, UK, pp. 289–309.
Bickel, W.K., Odum, A.L., Madden, G.J., 1999. Impulsivity and cigarette smoking: delay dis-
counting in current, never, and ex-smokers. Psychopharmacology (Berl) 146 (4), 447–454.
Bickel, W.K., Miller, M.L., Yi, R., Kowal, B.P., Lindquist, D.M., Pitcock, J.A., 2007. Behav-
ioral and neuroeconomics of drug addiction: competing neural systems and temporal dis-
counting processes. Drug Alcohol Depend. 90S, S85–S91.
Bickel, W.K., Jones, B.A., Landes, R.D., Christensen, D.R., Jackson, L., Mancino, M., 2010.
Hypothetical intertemporal choice and real economic behavior: delay discounting predicts
voucher redemptions during contingency-management procedures. Exp. Clin. Psycho-
pharmacol. 18 (6), 546–552.
Bickel, W.K., Jarmolowicz, D.P., Mueller, E.T., Gatchalian, K.M., 2011a. The behavioral eco-
nomics and neuroeconomics of reinforcer pathologies: implications for etiology and treat-
ment of addiction. Curr. Psychiatry Rep. 13 (5), 406–415.
Bickel, W.K., Landes, R.D., Christensen, D.R., et al., 2011b. Single- and cross-commodity
discounting among cocaine addicts: the commodity and its temporal location determine
discounting rate. Psychopharmacology (Berl) 217 (2), 177–187.
Bickel, W.K., Yi, R., Landes, R.D., Hill, P.F., Baxter, C., 2011c. Remember the future: work-
ing memory training decreases delay discounting among stimulant addicts. Biol. Psychi-
atry 69 (3), 260–265.
Bickel, W.K., Jarmolowicz, D.P., Mueller, E.T., Gatchalian, K.M., McClure, S.M., 2012a. Are
executive function and impulsivity antipodes? A conceptual reconstruction with special
reference to addiction. Psychopharmacology (Berl) 221 (3), 361–387.
Bickel, W.K., Jarmolowicz, D.P., Mueller, E.T., Koffarnus, M.N., Gatchalian, K.M., 2012b.
Excessive discounting of delayed reinforcers as a trans-disease process contributing to ad-
diction and other disease-related vulnerabilities: emerging evidence. Pharmacol. Ther.
134 (3), 287–297.
Bickel, W.K., Mueller, E.T., Jarmolowicz, D.P., 2013. What is addiction? In: McCrady, B.,
Epstein, E. (Eds.), Addictions: A Comprehensive Guidebook, second ed. Oxford
University Press, New York, pp. 3–16.
Bickel, W.K., Landes, R.D., Kurth-Nelson, Z., Redish, A.D., 2014a. A quantitative signature
of self-control repair: rate-dependent effects of successful addiction treatment. Clin. Psy-
chol. Sci. 2 (6), 685–695.
Bickel, W.K., Moody, L., Quisenberry, A.J., Ramey, C.T., Sheffer, C.E., 2014b. A competing
neurobehavioral decision systems model of SES-related health and behavioral disparities.
Prev. Med. 68, 37–43.
Bickel, W.K., Quisenberry, A.J., Moody, L., Wilson, A.G., 2015. Therapeutic opportunities
for self-control repair in addiction and related disorders: change and the limits of change
in trans-disease processes. Clin. Psychol. Sci. 3 (1), 140–153.
Bierut, L.J., Strickland, J.R., Thompson, J.R., Afful, S.E., Cottler, L.B., 2008. Drug use and
dependence in cocaine dependent subjects, community-based individuals, and their sib-
lings. Drug Alcohol Depend. 95, 14–22.
Bleiberg, J.L., Devlin, P., Croan, J., Briscoe, R., 1994. Relationship between treatment length
and outcome in a therapeutic community. Int. J. Addict. 29 (6), 729–740.
Bolla, K.I., Funderburk, F.R., Cadet, J.L., 2000. Differential effects of cocaine and cocaine
alcohol on neurocognitive performance. Neurology 54 (12), 2285–2292.
Brackins, T., Brahm, N.C., Kissack, J.C., 2011. Treatments for methamphetamine abuse: a
literature review for the clinician. J. Pharm. Pract. 24 (6), 541–550.
treatment brain activation during stroop task is associated with outcomes in cocaine-
dependent patients. Biol. Psychiatry 64 (11), 998–1004.
Budney, A.J., Higgins, S.T., Hughes, J.R., Bickel, W.K., 1993. Nicotine and caffeine use in
cocaine-dependent individuals. J. Subst. Abus. Treat. 5 (2), 117–130.
Buka, S.L., 2002. Disparities in health status and substance use: ethnicity and socioeconomic
factors. Public Health Rep. 117, S118–S125.
Burling, T.A., Salvio, M.A., Seidner, A.L., Ramsey, T.G., 1996. Cigarette smoking in alcohol
and cocaine abusers. J. Subst. Abus. 8 (4), 445–452.
Camprodon, J.A., Martinez-Raga, J., Alonso-Alonso, M., Shih, M.C., Pascual-Leone, A.,
2007. One session of high frequency repetitive transcranial magnetic stimulation (rtms)
to the right prefrontal cortex transiently reduces cocaine craving. Drug Alcohol Depend.
86 (1), 91–94.
References 287
Carroll, K.M., Onken, L.S., 2005. Behavioral therapies for drug abuse. Am. J. Psychiatry
162 (8), 1452–1460.
Carroll, K.M., Ball, S.A., Martino, S., et al., 2008. Computer-assisted delivery of cognitive-
behavioral therapy for addiction: a randomized trial of CBT4CBT. Am. J. Psychiatry
165 (7), 881–888.
Chesson, H.W., Leichliter, J.S., Zimet, G.D., Rosenthal, S.L., Bernstein, D.I., Fife, K.H., 2006.
Discount rates and risky sexual behavior among teenagers and young adults. J. Risk Un-
certain. 32 (3), 217–230.
Childress, A.R., Mozley, P.D., McElgin, W., Fitzgerald, J., Reivich, M., O’Brien, C.P., 1999.
Limbic activation during cue-induced cocaine craving. Am. J. Psychiatr. 156 (1), 11–18.
Cho, S.S., Koshimori, Y., Aminian, K., et al., 2015. Investing in the future: stimulation of
the medial prefrontal cortex reduces discounting of delayed rewards. Neuropsycho-
pharmacology 40 (3), 546–553.
Dackis, C.A., Kampman, K.M., Lynch, K.G., et al., 2012. A double-blind, placebo-controlled
trial of modafinil for cocaine dependence. J. Subst. Abus. Treat. 43 (3), 303–312.
Dalley, J.W., Everitt, B.J., Robbins, T.W., 2011. Impulsivity, compulsivity, and top-down
cognitive control. Neuron 69 (4), 680–694.
Daniel, T.O., Stanton, C.M., Epstein, L.H., 2013. The future is now: reducing impulsivity and
energy intake using episodic future thinking. Psychol. Sci. 24 (11), 2339–2342.
de Vito, S., Gamboz, N., Brandimonte, M.A., Barone, P., Amboni, M., Della, Sala S., 2012.
Future thinking in Parkinson’s disease: an executive function? Neuropsychologia 50 (7),
1494–1501.
Eichhammer, P., Johann, M., Kharraz, A., et al., 2003. High-frequency repetitive transcra-
nial magnetic stimulation decreases cigarette smoking. J. Clin. Psychiatry 64 (8),
951–953.
Epstein, D.H., Hawkins, W.E., Covi, L., Umbricht, A., Preston, K.L., 2003. Cognitive-
behavioral therapy plus contingency management for cocaine use: findings during treat-
ment and across 12-month follow-up. Psychol. Addict. Behav. 17 (1), 73–82.
Ernst, M., Nelson, E.E., Jazbec, S., et al., 2005. Amygdala and nucleus accumbens in re-
sponse to receipt and omission of gains in adults and adolescents. Neuroimage 25 (4),
1279–1291.
Ersche, K.D., Turton, A.J., Chamberlain, S.R., Muller, U., Bullmore, E.T., Robbins, T.W.,
2012. Cognitive dysfunction and anxious-impulsive personality traits are endophenotypes
for drug dependence. Am. J. Psychiatry 169 (9), 926–936.
Evans, J.S., 2008. Dual-processing accounts of reasoning, judgment, and social cognition.
Annu. Rev. Psychol. 59, 255–278.
Evans, J.S., Stanovich, K.E., 2013. Dual-process theories of higher cognition-advancing the
debate. Perspect. Psychol. Sci. 8 (3), 223–241.
Everitt, B.J., Belin, D., Economidou, D., Pelloux, Y., Dalley, J.W., Robbins, T.W., 2008. Neu-
ral mechanisms underlying the vulnerability to develop compulsive drug-seeking habits
and addiction. Philos. Trans. R. Soc. B 363 (1507), 3125–3135.
Fitzgerald, P.B., Fountain, S., Daskalakis, Z.J., 2006. A comprehensive review of the effects of
rTMS on motor cortical excitability and inhibition. Clin. Neurophysiol. 117 (12),
2584–2596.
Franklin, T.R., Acton, P.D., Maldjian, J.A., et al., 2002. Decreased gray matter concentration
in the insular, orbitofrontal, cingulate, and temporal cortices of cocaine patients. Biol. Psy-
chiatry 51 (2), 134–142.
Galvan, A., Hare, T.A., Parra, C.E., et al., 2006. Earlier development of the accumbens relative
to orbitofrontal cortex might underlie risk-taking behavior in adolescents. J. Neurosci.
26 (25), 6885–6892.
Garavan, H., Pankiewicz, J., Bloom, A., et al., 2000. Cue-induced cocaine craving: neuroan-
atomical specificity for drug users and drug stimuli. Am. J. Psychiatr. 157 (11),
1789–1798. November 1, 2000.
Gerlach, K.D., Spreng, R.N., Gilmore, A.W., Schacter, D.L., 2011. Solving future problems:
default network and executive activity associated with goal-directed mental simulations.
Neuroimage 55 (4), 1816–1824.
Goldstein, R.Z., Volkow, N.D., 2002. Drug addiction and its underlying neurobiological basis:
neuroimaging evidence for the involvement of the frontal cortex. Am. J. Psychiatr.
159 (10), 1642–1652.
Goldstein, R.Z., Volkow, N.D., 2011. Dysfunction of the prefrontal cortex in addiction: neu-
roimaging findings and clinical implications. Nat. Rev. Neurosci. 12 (11), 652–669.
Goldstein, R.Z., Leskovjan, A.C., Hoff, A.L., et al., 2004. Severity of neuropsychological im-
pairment in cocaine and alcohol addiction: association with metabolism in the prefrontal
cortex. Neuropsychologia 42 (11), 1447–1458.
Goldstein, R.Z., Woicik, P.A., Maloney, T., et al., 2010. Oral methylphenidate normalizes cin-
gulate activity in cocaine addiction during a salient cognitive task. Proc. Natl. Acad. Sci.
U. S. A. 107 (38), 16667–16672.
Gorelick, D.A., Zangen, A., George, M.S., 2014. Transcranial magnetic stimulation in the
treatment of substance addiction. Ann. N. Y. Acad. Sci. 1327, 79–93.
Goudriaan, A.E., Veltman, D.J., van den Brink, W., Dom, G., Schmaal, L., 2013. Neurophys-
iological effects of modafinil on cue-exposure in cocaine dependence: a randomized
placebo-controlled cross-over study using pharmacological fMRI. Addict. Behav.
38 (2), 1509–1517.
Grabowski, J., Roache, J.D., Schmitz, J.M., Rhoades, H., Creson, D., Korszun, A., 1997. Re-
placement medication for cocaine dependence: methylphenidate. J. Clin. Psychopharma-
col. 17 (6), 485–488.
Hanlon, C.A., Dowdle, L.T., Austelle, C.W., et al., 2015. What goes up, can come down: novel
brain stimulation paradigms may attenuate craving and craving-related neural circuitry in
substance dependent individuals. Brain Res. In press.
Hart, C.L., Haney, M., Vosburg, S.K., Rubin, E., Foltin, R.W., 2008. Smoked cocaine self-
administration is decreased by modafinil. Neuropsychopharmacology 33 (4), 761–768.
Haushofer, J., Fehr, E., 2014. On the psychology of poverty. Science 344 (6186), 862–867.
Heil, S.H., Johnson, M.W., Higgins, S.T., Bickel, W.K., 2006. Delay discounting in currently
using and currently abstinent cocaine-dependent outpatients and non-drug-using matched
controls. Addict. Behav. 31 (7), 1290–1294.
Herremans, S.C., Baeken, C., Vanderbruggen, N., et al., 2012. No influence of one right-sided
prefrontal hf-rtms session on alcohol craving in recently detoxified alcohol-dependent pa-
tients: results of a naturalistic study. Drug Alcohol Depend. 120 (1–3), 209–213.
Herremans, S.C., Vanderhasselt, M.A., De Raedt, R., Baeken, C., 2013. Reduced intra-
individual reaction time variability during a Go-NoGo task in detoxified alcohol-
dependent patients after one right-sided dorsolateral prefrontal HF-rTMS session. Alcohol
Alcohol. 48 (5), 552–557.
Higgins, S.T., Delaney, D.D., Budney, A.J., et al., 1991. A behavioral approach to achieving
initial cocaine abstinence. Am. J. Psychiatr. 148 (9), 1218–1224.
References 289
Higgins, S.T., Budney, A.J., Bickel, W.K., Foerg, F.E., Donham, R., Badger, G.J., 1994. In-
centives improve outcome in outpatient behavioral treatment of cocaine dependence.
Arch. Gen. Psychiatry 51 (7), 568–576.
Higgins, S.T., Budney, A.J., Bickel, W.K., Badger, G., Foerg, F., Ogden, D., 1995. Outpatient
behavioral treatment for cocaine dependence: one-year outcome. Exp. Clin. Psychophar-
macol. 3 (2), 205–212.
Hiscock, R., Bauld, L., Amos, A., Fidler, J.A., Munafo, M., 2012. Socioeconomic status and
smoking: a review. Ann. N. Y. Acad. Sci. 1248, 107–123.
Hoogendam, J.M., Ramakers, G.M., Di Lazzaro, V., 2010. Physiology of repetitive transcra-
nial magnetic stimulation of the human brain. Brain Stimul. 3 (2), 95–118.
Hoppner, J., Broese, T., Wendler, L., Berger, C., Thome, J., 2011. Repetitive transcranial mag-
netic stimulation (rTMS) for treatment of alcohol dependence. World J. Biol. Psychiatry
12 (Suppl. 1), 57–62.
cology (Berl) 146 (4), 373–390.
Johnson, M.W., Bruner, N.R., 2012. The sexual discounting task: HIV risk behavior and the
discounting of delayed sexual rewards in cocaine dependence. Drug Alcohol Depend.
123 (1–3), 15–21.
Jovanovski, D., Erb, S., Zakzanis, K.K., 2005. Neurocognitive deficits in cocaine users: a
quantitative review of the evidence. J. Clin. Exp. Neuropsychol. 27 (2), 189–204.
Kalechstein, A.D., Mahoney 3rd, J.J., Yoon, J.H., Bennett, R., De la Garza 2nd, R., 2013. Mod-
afinil, but not escitalopram, improves working memory and sustained attention in long-
term, high-dose cocaine users. Neuropharmacology 64, 472–478.
Kalivas, P.W., Volkow, N.D., 2005. The neural basis of addiction: a pathology of motivation
and choice. Am. J. Psychiatry 162 (8), 1403–1413.
Khurana, A., Romer, D., Betancourt, L.M., Brodsky, N.L., Giannetta, J.M., Hurt, H., 2015.
Experimentation versus progression in adolescent drug use: a test of an emerging neuro-
behavioral imbalance model. Dev. Psychopathol. 27, 901–913.
Koffarnus, M.N., Jarmolowicz, D.P., Mueller, E.T., Bickel, W.K., 2013. Changing delay dis-
counting in the light of the competing neurobehavioral decision systems theory: a review.
J. Exp. Anal. Behav. 99 (1), 32–57.
Konova, A.B., Moeller, S.J., Tomasi, D., Volkow, N.D., Goldstein, R.Z., 2013. Effects of
methylphenidate on resting-state functional connectivity of the mesocorticolimbic dopa-
mine pathways in cocaine addiction. JAMA Psychiatry 70 (8), 857–868.
Kubler, A., Murphy, K., Garavan, H., 2005. Cocaine dependence and attention switching
within and between verbal and visuospatial working memory. Eur. J. Neurosci. 21 (7),
1984–1992.
Li, X., Hartwell, K.J., Owens, M., et al., 2013. Repetitive transcranial magnetic stimulation of
the dorsolateral prefrontal cortex reduces nicotine cue craving. Biol. Psychiatry 73 (8),
714–720.
Lopez-Quintero, C., Perez de los Cobos, J., Hasin, D.S., et al., 2011. Probability and predictors
of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: re-
sults of the national epidemiologic survey on alcohol and related conditions (NESARC).
Drug Alcohol Depend. 115 (1–2), 120–130.
Lucantonio, F., Stalnaker, T.A., Shaham, Y., Niv, Y., Schoenbaum, G., 2012. The impact of
orbitofrontal dysfunction on cocaine addiction. Nat. Neurosci. 15 (3), 358–366.
Lussier, J.P., Heil, S.H., Mongeon, J.A., Badger, G.J., Higgins, S.T., 2006. A meta-analysis of
voucher-based reinforcement therapy for substance use disorders. Addiction 101 (2),
192–203.
Madden, G.J., Petry, N.M., Badger, G.J., Bickel, W.K., 1997. Impulsive and self-control
choices in opioid-dependent patients and non-drug-using control participants: drug and
monetary rewards. Exp. Clin. Psychopharmacol. 5 (3), 256–262.
Makris, N., Gasic, G.P., Seidman, L.J., et al., 2004. Decreased absolute amygdala volume in
cocaine addicts. Neuron 44 (4), 729–740.
Mani, A., Mullainathan, S., Shafir, E., Zhao, J., 2013. Poverty impedes cognitive function.
Science 341 (6149), 976–980.
Mariani, J.J., Levin, F.R., 2012. Psychostimulant treatment of cocaine dependence. Psychiatr.
Clin. North Am. 35 (2), 425–439.
Maude-Griffin, P.M., Hohenstein, J.M., Humfleet, G.L., Reilly, P.M., Tusel, D.J., Hall, S.M.,
1998. Superior efficacy of cognitive-behavioral therapy for urban crack cocaine abusers:
main and matching effects. J. Consult. Clin. Psychol. 66 (5), 832–837.
Mazur, J.E., 1987. An adjusting procedure for studying delayed reinforcement. In:
Commons, M.L., Mazur, J.E., Nevin, J.A., Rachlin, H. (Eds.), Quantitative Analyses of
Behavior, vol. 5. Erlbaum, Hillsdale, NJ, pp. 55–73.
McClure, S.M., Bickel, W.K., 2014. A dual-systems perspective on addiction:
contributions from neuroimaging and cognitive training. Ann. N. Y. Acad. Sci. 1327,
62–78.
McClure, S.M., Laibson, D.I., Loewenstein, G., Cohen, J.D., 2004. Separate neural systems
value immediate and delayed monetary rewards. Science 306 (5695), 503–507. October
15, 2004.
McClure, S.M., Ericson, K.M., Laibson, D.I., Loewenstein, G., Cohen, J.D., 2007. Time dis-
counting for primary rewards. J. Neurosci. 27 (21), 5796–5804.
Metcalfe, J., Mischel, W., 1999. A hot/cold-system analysis of delay of gratification: dynamics
of willpower. Psychol. Rev. 106 (1), 3–19.
Miech, R., 2008. The formation of a socioeconomic health disparity: the case of cocaine use
during the 1980s and 1990s. J. Health Soc. Behav. 49 (3), 352–366.
Miller, E.K., Cohen, J.D., 2001. An integrative theory of prefrontal cortex function. Annu.
Rev. Neurosci. 24 (1), 167–202.
Mishra, B.R., Nizamie, S.H., Das, B., Praharaj, S.K., 2010. Efficacy of repetitive transcranial
magnetic stimulation in alcohol dependence: a sham-controlled study. Addiction 105 (1),
49–55.
Moeller, F.G., Dougherty, D.M., Barratt, E.S., Schmitz, J.M., Swann, A.C., Grabowski, J.,
2001. The impact of impulsivity on cocaine use and retention in treatment. J. Subst. Abus.
Treat. 21 (4), 193–198.
Moeller, F.G., Hasan, K.M., Steinberg, J.L., et al., 2005. Reduced anterior corpus callosum
white matter integrity is related to increased impulsivity and reduced discriminability
in cocaine-dependent subjects: diffusion tensor imaging. Neuropsychopharmacology
30 (3), 610–617.
Moeller, F.G., Schmitz, J.M., Herin, D., Kjome, K.L., 2008. Use of stimulants to treat cocaine
and methamphetamine abuse. Curr. Psychiatry Rep. 10 (5), 385–391.
Moeller, F.G., Steinberg, J.L., Schmitz, J.M., et al., 2010. Working memory fMRI activation in
cocaine-dependent subjects: association with treatment response. Psychiatry Res. 181 (3),
174–182.
References 291
Moeller, S.J., Tomasi, D., Honorio, J., Volkow, N.D., Goldstein, R.Z., 2012. Dopaminergic
involvement during mental fatigue in health and cocaine addiction. Transl. Psychiatry
2, e176.
Moreno-Lopez, L., Catena, A., Fernandez-Serrano, M.J., et al., 2012. Trait impulsivity and
prefrontal gray matter reductions in cocaine dependent individuals. Drug Alcohol Depend.
125 (3), 208–214.
Narvaez, J.C., Jansen, K., Pinheiro, R.T., et al., 2014. Psychiatric and substance-use comor-
bidities associated with lifetime crack cocaine use in young adults in the general popula-
tion. Compr. Psychiatry 55 (6), 1369–1376.
Noble, K.G., Houston, S.M., Kan, E., Sowell, E.R., 2012. Neural correlates of socioeconomic
status in the developing human brain. Dev. Sci. 15 (4), 516–527.
Noel, X., Brevers, D., Bechara, A., 2013. A neurocognitive approach to understanding the neu-
robiology of addiction. Curr. Opin. Neurobiol. 23 (4), 632–638.
Okuda, J., Fujii, T., Ohtake, H., et al., 2003. Thinking of the future and the past: the roles of the
frontal pole and the medial temporal lobes. Neuroimage 19 (4), 1369–1380.
Olesen, P.J., Westerberg, H., Klingberg, T., 2004. Increased prefrontal and parietal activity
after training of working memory. Nat. Neurosci. 7 (1), 75–79.
Palamar, J.J., Davies, S., Ompad, D.C., Cleland, C.M., Weitzman, M., 2015. Powder cocaine
and crack use in the United States: an examination of risk for arrest and socioeconomic
disparities in use. Drug Alcohol Depend. 149, 108–116.
Pampel, F.C., Krueger, P.M., Denney, J.T., 2010. Socioeconomic disparities in health behav-
iors. Annu. Rev. Sociol. 36, 349–370.
Peters, J., Buchel, C., 2010. Episodic future thinking reduces reward delay discounting through
an enhancement of prefrontal-mediotemporal interactions. Neuron 66 (1), 138–148.
Petry, N.M., 2001. Delay discounting of money and alcohol in actively using alcoholics, cur-
rently abstinent alcoholics, and controls. Psychopharmacology (Berl) 154 (3), 243–250.
Petry, N.M., Martin, B., 2002. Low-cost contingency management for treating cocaine- and
opioid-abusing methadone patients. J. Consult. Clin. Psychol. 70 (2), 398–405.
Petry, N.M., Tedford, J., Austin, M., Nich, C., Carroll, K.M., Rounsaville, B.J., 2004. Prize
reinforcement contingency management for treating cocaine users: how low can we go,
and with whom? Addiction 99 (3), 349–360.
Poincaré, H., 1905. Science and Hypothesis. The Walter Scott Publishing Company, Ltd.,
New York.
Poling, J., Oliveto, A., Petry, N., et al., 2006. Six-month trial of bupropion with contingency
management for cocaine dependence in a methadone-maintained population. Arch. Gen.
Psychiatry 63 (2), 219–228.
Politi, E., Fauci, E., Santoro, A., Smeraldi, E., 2008. Daily sessions of transcranial magnetic
stimulation to the left prefrontal cortex gradually reduce cocaine craving. Am. J. Addict.
17 (4), 345–346.
Prendergast, M., Podus, D., Finney, J., Greenwell, L., Roll, J., 2006. Contingency management
for treatment of substance use disorders: a meta-analysis. Addiction 101 (11), 1546–1560.
Pripfl, J., Tomova, L., Riecansky, I., Lamm, C., 2014. Transcranial magnetic stimulation of the
left dorsolateral prefrontal cortex decreases cue-induced nicotine craving and EEG delta
power. Brain Stimul. 7 (2), 226–233.
Rawson, R.A., Huber, A., McCann, M., et al., 2002. A comparison of contingency manage-
ment and cognitive-behavioral approaches during methadone maintenance treatment for
cocaine dependence. Arch. Gen. Psychiatry 59 (9), 817–824.
sensitization theory of addiction. Brain Res. Rev. 18 (3), 247–291.
Robles, E., Silverman, K., Preston, K.L., et al., 2000. The brief abstinence test: voucher-based
reinforcement of cocaine abstinence. Drug Alcohol Depend. 58 (1–2), 205–212.
Rush, C.R., Stoops, W.W., Hays, L.R., 2009. Cocaine effects during D-amphetamine mainte-
nance: a human laboratory analysis of safety, tolerability and efficacy. Drug Alcohol De-
pend. 99 (1–3), 261–271.
Sanfey, A.G., Chang, L.J., 2008. Multiple systems in decision making. Ann. N. Y. Acad. Sci.
1128, 53–62.
Schmaal, L., Goudriaan, A.E., Joos, L., et al., 2014. Neural substrates of impulsive decision
making modulated by modafinil in alcohol-dependent patients. Psychol. Med. 44 (13),
2787–2798.
Shearer, J., Wodak, A., van Beek, I., Mattick, R.P., Lewis, J., 2003. Pilot randomized double
blind placebo-controlled study of dexamphetamine for cocaine dependence. Addiction
98 (8), 1137–1141.
Simpson, D.D., Joe, G.W., Fletcher, B.W., Hubbard, R.L., Anglin, M.D., 1999. A national
evaluation of treatment outcomes for cocaine dependence. Arch. Gen. Psychiatry
56 (6), 507–514.
Sisk, C.L., Zehr, J.L., 2005. Pubertal hormones organize the adolescent brain and behavior.
Front. Neuroendocrinol. 26 (3–4), 163–174.
Sofis, M.J., Jarmolowicz, D.P., Martin, L.E., 2014. Competing neurobehavioral decision sys-
tems and the neuroeconomics of craving in opioid addiction. Neurosci. Neuroecon.
3, 87–89.
Sofuoglu, M., 2010. Cognitive enhancement as a pharmacotherapy target for stimulant addic-
tion. Addiction 105 (1), 38–48.
Sowell, E.R., Peterson, B.S., Thompson, P.M., Welcome, S.E., Henkenius, A.L., Toga, A.W.,
2003. Mapping cortical change across the human life span. Nat. Neurosci. 6 (3), 309–315.
Steinberg, L., 2007. Risk taking in adolescence: new perspectives from brain and behavioral
science. Curr. Dir. Psychol. Sci. 16 (2), 55–59.
Steinberg, L., Albert, D., Cauffman, E., Banich, M., Graham, S., 2008. Age differences in sen-
sation seeking and impulsivity as indexed by behavior and self-report: evidence for a dual
systems model. Dev. Psychol. 44 (6), 1764–1778.
Stoops, W.W., Blackburn, J.W., Hudson, D.A., Hays, L.R., Rush, C.R., 2008. Safety, tolera-
bility and subject-rated effects of acute intranasal cocaine administration during atomox-
etine maintenance. Drug Alcohol Depend. 92 (1–3), 282–285.
Streeter, C.C., Terhune, D.B., Whitfield, T.H., et al., 2008. Performance on the stroop predicts
treatment compliance in cocaine-dependent individuals. Neuropsychopharmacology
33 (4), 827–836.
Substance Abuse and Mental Health Services Administration, 2004. Results from the 2003
National Survey on Drug Use and Health: National Findings. Office of Applied
Studies, Rockville, MD. SMA 04 3964.
Substance Abuse and Mental Health Services Administration, 2013. Results from the 2013
National Survey on Drug Use and Health: Summary of National Findings. Office of
Applied Studies, Rockville, MD. SMA 14-4863.
Teicher, M.H., Andersen, S.L., Hostetter Jr., J.C., 1995. Evidence for dopamine receptor prun-
ing between adolescence and adulthood in striatum but not nucleus accumbens. Brain Res.
Dev. Brain Res. 89 (2), 167–172.
References 293
Thickbroom, G.W., 2007. Transcranial magnetic stimulation and synaptic plasticity: experi-
mental framework and human models. Exp. Brain Res. 180 (4), 583–593.
Turner, D.C., Clark, L., Dowson, J., Robbins, T.W., Sahakian, B.J., 2004. Modafinil improves
cognition and response inhibition in adult attention-deficit/hyperactivity disorder. Biol.
Psychiatry 55 (10), 1031–1040.
Vansickel, A.R., Fillmorex, M.T., Hays, L.R., Rush, C.R., 2008. Effects of potential agonist-
replacement therapies for stimulant dependence on inhibitory control in cocaine abusers.
Am. J. Drug Alcohol Abuse 34 (3), 293–305.
Volkow, N.D., Fowler, J.S., Wang, G.J., et al., 1993. Decreased dopamine D2 receptor avail-
ability is associated with reduced frontal metabolism in cocaine abusers. Synapse 14 (2),
169–177.
Volkow, N.D., Wang, G.J., Fowler, J.S., et al., 1999. Prediction of reinforcing responses to
psychostimulants in humans by brain dopamine D2 receptor levels. Am. J. Psychiatry
156 (9), 1440–1443.
Volkow, N.D., Wang, G.J., Ma, Y., et al., 2005. Activation of orbital and medial prefrontal
cortex by methylphenidate in cocaine-addicted subjects but not in controls: relevance
to addiction. J. Neurosci. 25 (15), 3932–3939.
Wagner, F.A., Anthony, J.C., 2002. From first drug use to drug dependence; developmental
periods of risk for dependence upon marijuana, cocaine, and alcohol.
Wesley, M.J., Bickel, W.K., 2014. Remember the future II: meta-analyses and functional over-
lap of working memory and delay discounting. Biol. Psychiatry 75 (6), 435–448.
Wilcox, C.E., Teshiba, T.M., Merideth, F., Ling, J.Y., Mayer, A.R., 2011. Enhanced cue re-
activity and fronto-striatal functional connectivity in cocaine use disorders. Drug Alcohol
Depend. 1115 (1), 137–144.
Wilkinson, R., Pickett, K., 2011. Greater equality: the hidden key to better health and higher
scores. Am. Educ. 35 (1), 5–9.
Wing, V.C., Barr, M.S., Wass, C.E., et al., 2013. Brain stimulation methods to treat tobacco
addiction. Brain Stimul. 6 (3), 221–230.
Worhunsky, P.D., Stevens, M.C., Carroll, K.M., et al., 2013. Functional brain networks asso-
ciated with cognitive control, cocaine dependence, and treatment outcome. Psychol. Ad-
dict. Behav. 27 (2), 477–488.
Xu, J., DeVito, E.E., Worhunsky, P.D., Carroll, K.M., Rounsaville, B.J., Potenza, M.N., 2010.
White matter integrity is associated with treatment outcome measures in cocaine depen-
dence. Neuropsychopharmacology 35 (7), 1541–1549.
Yoon, J.H., Newton, T.F., Haile, C.N., et al., 2013. Effects of d-cycloserine on cue-induced
craving and cigarette smoking among concurrent cocaine- and nicotine-dependent volun-
teers. Addict. Behav. 38, 1518–1526.
Ziemann, U., Paulus, W., Nitsche, M.A., et al., 2008. Consensus: motor cortex plasticity pro-
tocols. Brain Stimul. 1 (3), 164–182.
CHAPTER
Clinical neuroscience of
amphetamine-type
stimulants: From basic
science to treatment
15
development
Kelly E. Courtney, Lara A. Ray1
1
Abstract
Abuse of amphetamine-type stimulants (ATS) poses a significant public health concern with
known neurotoxic and neurocognitive effects to the user. In this chapter, we seek to integrate
the latest research on ATS, particularly methamphetamine, by covering areas of pharmacol-
ogy, neurocognitive effects, and the treatment of ATS use disorders with the goal of advancing
the clinical neuroscience of ATS and highlighting avenues for future research.
Keywords
Amphetamine, Stimulants, Methamphetamine, Addiction, Clinical neuroscience, Treatment,
ATS use disorders
1 INTRODUCTION
Amphetamine-type stimulants (ATS), including amphetamine, dextroamphetamine
(D-amphetamine), methamphetamine, and amphetamine-like drugs such as methyl-
phenidate, have a long history of use in the United States (U.S.) and continue to pose
a significant public health concern in the U.S. and worldwide. Synthetic amphet-
amine was first popularized in the U.S. in the 1930s as an over-the-counter nasal de-
congestant and was used to reduce fatigue and suppress appetite during World War
II. In the 1950s and 1960s, amphetamine was commonly prescribed as a medication
for depression and obesity, with approximately 31 million prescriptions filled in the
U.S. in 1967 (Anglin et al., 2000). Shortly thereafter, legislation was passed in
295
296 CHAPTER 15 ATS clinical neuroscience
attempt to restrict the availability of amphetamine, and medicinal use began to de-
cline (Gonzales et al., 2010); however, this reclassification of amphetamine to a more
restrictive schedule led to a surge in illicit manufacturing and use of methamphet-
amine. Furthermore, the relatively recent increase in attention deficit hyperactivity
disorder diagnoses has been accompanied by a resurgence of prescriptions for stim-
ulant medications with diversion of these medications a growing concern for the na-
tion (Rabiner, 2013). Despite multiple legislative attempts to limit public access,
illicit ATS use remains highly prevalent.
Currently, ATS are the second most commonly used class of illicit drugs world-
wide (UNODC, World Drug Report 2012); approximately 0.7% of the global pop-
ulation (33.8 million people) aged 15–64 years old reported using an ATS in 2010
(UNODC, World Drug Report 2013). In the U.S., estimates from 2013 suggest over
21.7 million people ages 12 years and older (8.3% of total responders) have used
ATS for nonmedical purposes in their lifetimes, 3.5 million people (1.3%) reported
past year use, and approximately 1.4 million (0.5%) of those identified as past month
users. Further, 12 million (4.7%) of the individuals surveyed reported lifetime use of
methamphetamine specifically, with approximately 440,000 (0.2%) of those identi-
fied as past month users (Substance Abuse and Mental Health Services
Administration (SAMHSA), 2013a). Importantly, these estimates appear to be grow-
ing both in terms of supply and demand (UNODC, 2013).
Subsequently, the prevalence of ATS use disorders is also on the rise. In 2012,
535,000 (0.2%) individuals were estimated to meet the Diagnostic and Statistical
Manual of Mental Disorders (4th ed., DSM–IV; American Psychiatric
Association, 1994) criteria of ATS abuse or dependence, a significant increase from
the 329,000 (0.1%) in 2011 (SAMHSA, 2013a). This increase was especially pro-
nounced among individuals aged 18–25 years, with 0.5% meeting criteria in
2012, up from 0.3% in 2011. Furthermore, primary methamphetamine/amphetamine
treatment admissions were more likely than all drug treatment admissions combined
to receive long-term rehabilitation/residential treatment (16% vs. 7%) (SAMHSA,
2013b), suggestive of the exceedingly high costs associated with the treatment of
ATS use disorders and underscoring the need for more efficacious, cost effective,
and easily deliverable treatments.
Developing a greater understanding of the clinical neuroscience underlying the
consequences of ATS use is an important step toward the development of more ef-
ficacious treatments for ATS use disorders. This is especially important with respect
to medications development given the lack of any current FDA-approved medica-
tions for ATS dependence. Significant advances in preclinical and clinical research
have begun to identify the neurochemical pathways affected by ATS use and high-
light potential targets for intervention. Thus, knowledge of the pharmacological and
neurological adaptations associated with ATS use could lead to the development of
more efficacious medications and further inform psychosocial interventions for ATS
use disorders (Table 1).
Given that methamphetamine is the most frequently used ATS worldwide
(UNODC, 2013), and that studies of neurodegeneration, neurocognitive functioning,
2 Pharmacology and neurotoxicity 297
Table 1 Chapter Highlights

• Amphetamine-type stimulants (ATS) are the second most commonly used class of illicit
drugs worldwide and the prevalence of ATS use disorders are on the rise
• ATS have pervasive, and potentially long-lasting effects on the dopaminergic,
noradrenergic, serotonergic, and opioidergic neurotransmitter systems throughout the
brain and can result in detrimental effects to cognitive processes in heavy users
• More efficacious treatment options, such as FDA-approved pharmacotherapies, are
greatly needed for ATS use disorders
• Promising medications currently under study for the treatment of ATS use disorders include
oxytocin, bupropion, mirtazapine, topiramate, modafinil, and naltrexone
• The integration of basic neuroscience and treatment development research could improve
clinical outcomes in ATS use disorders by facilitating targeted treatment approaches
and treatment most commonly target methamphetamine using populations, the ma-
jority of this chapter presents the current understanding of the clinical neuroscience
behind methamphetamine use and associated disorders, expanded to ATS more
broadly where applicable.
2 PHARMACOLOGY AND NEUROTOXICITY

As with most ATS, methamphetamine stimulates the release, and partially blocks the
reuptake, of newly synthesized catecholamines in the CNS (Cho and Melega, 2002).
Due to its structural similarity, methamphetamine interacts with the dopamine trans-
porter (DAT), noradrenaline transporter (NET), serotonin transporter (SERT), and
vesicular monoamine transporter-2 (VMAT-2) and reverses their endogenous func-
tion, thereby redistributing monoamines from storage vesicles into the cytosol. This
process results in the release of dopamine, noradrenaline, and serotonin into the syn-
apse, which then stimulate postsynaptic monoamine receptors (Cruickshank and
Dyer, 2009). Methamphetamine also attenuates the metabolism of monoamines
by inhibiting monoamine oxidase (Sulzer et al., 2005), further enabling the buildup
of excess monoamines in the synapse.
The monoamines released due to the presence of ATS act on the major noradren-
ergic, serotonergic, and dopaminergic pathways of the brain. The medial basal fore-
brain, the hippocampus, as well as the prefrontal cortex (PFC) represent
noradrenergic regions of interest for ATS effects, with various affected functions re-
lated to arousal, memory consolidation, and cognitive processing, respectively
(Berridge and Waterhouse, 2003). Affected serotonergic neurons are dispersed
throughout the brain, regulating diverse functions such as respiration, pain percep-
tion, sexual drive, reward, and higher-order cognitive processing (Hornung, 2003).
In the case of dopamine, methamphetamine activates the mesolimbic, mesocortical
circuit, and the nigrostriatal pathways, which have been related to the euphoric ef-
fects observed immediately after the ingestion of the drug (Homer et al., 2008).
Although no differences in striatal dopamine release between amphetamine and

methamphetamine are observed (Melega et al., 1995), amphetamine is thought to
result in a slightly greater dopamine release in the PFC, which may be responsible
for the subtle differences between these drugs on behavioral tolerance and working
memory measures (Shoblock et al., 2003a,b).
Repeated exposure to moderate to high levels of methamphetamine has been re-
lated to neurotoxic effects on the dopaminergic and serotonergic systems, leading to
potentially irreversible loss of nerve terminals and/or neuron cell bodies (Cho and
Melega, 2002). Preclinical evidence suggests that D-amphetamine, even when ad-
ministered at commonly prescribed therapeutic doses, also results in toxicity to brain
dopaminergic axon terminals (Ricaurte et al., 2005). Although the precise mecha-
nisms remain unclear, the culmination of evidence suggests that the high level of
cytoplasmic dopamine released as a result of ATS use leads to the accumulation
of reactive oxygen species and severe oxidative stress on the neuron (Berman
et al., 2008). Furthermore, frequent use of methamphetamine has been associated
with reductions in striatal D2-receptor availability (Groman et al., 2012; Volkow
et al., 2001a), VMAT-2 density ( Johanson et al., 2006), SERT density (Sekine
et al., 2006), and DAT site density (McCann et al., 1998; Villemagne et al., 1998;
Volkow et al., 2001b,c), with some markers (i.e., DAT density) showing improve-
ment following prolonged (greater than 12 months) abstinence (Volkow et al.,
2001b). Reduced markers of neuronal integrity and increased markers of glial con-
tent are also observed in chronic methamphetamine abusers, possibly indicating
the proliferation of glial cells following neural damage (Chang et al., 2007; Ernst
et al., 2000).
The potentiation of dopaminergic neurotransmission within the mesocorticolim-
bic circuit is thought to underlie the reinforcing properties of drugs of abuse, al-
though evidence is accumulating on a converging role of the endogenous opioid
systems in the establishment of reinforcement (Boutrel, 2008). In terms of neuroanat-
omy, endogenous opioid receptors are widely distributed throughout the CNS, with
differential distributions per opioid receptor type. Importantly, opioid receptors and
peptides are highly expressed in brain areas involved in reward and motivation, such
as the ventral tegmental area (VTA) and nucleus accumbens (NAcc) (Mansour et al.,
1995). Administration of classical exogenous opioids facilitates dopamine release in
the mesolimbic reward system by activating m- and d-opioid receptors in the NAcc
(Hirose et al., 2005; Murakawa et al., 2004) and by decreasing GABA-inhibition via
m- and k-opioid receptors, which are mainly located on GABA interneurons in the
VTA (Bonci and Williams, 1997; Shoji et al., 1999). Many nonopioid drugs of abuse,
including ATS, are also known to interact with the endogenous opioid system (for a
review, see Trigo et al., 2010), and this interaction may mediate some of the reward-
ing properties associated with acute ATS use (Boutrel, 2008). For example, acute
amphetamine administration has been linked with increased b-endorphin levels in
the NAcc (Olive et al., 2001), increased striatonigral dynorphin-like immunoreactiv-
ity (Bustamante et al., 2002; Hanson et al., 1988), and changes in the endogenous
opioid mRNA expression in the striatum (Hurd and Herkenham, 1992; Smith and
3 Neurocognitive effects 299
McGinty, 1994; Wang and McGinty, 1995). Further, preclinical data suggest that the
endogenous opioid system is involved in the induction and expression of
methamphetamine-induced behavioral (locomotor) sensitization (Chiu et al.,
2006), analogous to compulsive drug-seeking behavior in humans (i.e., drug craving;
Itzhak and Ali, 2002), through its modulatory actions of the mesolimbic dopamine
system (Ford et al., 2006).
In summary, methamphetamine and other ATS have pervasive and potentially
long-lasting effects not only on the dopaminergic system but also on noradrenergic,
serotonergic, and opioidergic neurotransmitter systems throughout the brain. It is
through the culmination of these complex neurochemical modulations that signifi-
cant behavioral and cognitive changes result.
3 NEUROCOGNITIVE EFFECTS
Many ATS are used therapeutically to improve attention and cognition; however, a
review of the literature suggests dosage, and route of administration is a key deter-
minant of the cognitive effects of these drugs (see Wood et al., 2014). Wood et al.
(2014) argue that cognitive effects of ATS, including prescription medications such
as D-amphetamine and methylphenidate, follow an inverted U dose–response curve,
such that high doses result in detrimental effects on cognitive processing in domains
such as learning and memory. In fact, a recent study of frequent recreational users of
D-amphetamine observed impairments in performance on executive functioning and
memory consolidation tasks, in addition to a trend toward reduced striatal DAT site
binding and a blunted hemodynamic response to methylphenidate challenge, when
compared to healthy controls (Schouw et al., 2013).
Chronic methamphetamine use, more specifically, has been associated with al-
terations across a broad spectrum of neurocognitive processes, although differenti-
ating preexisting deficits from methamphetamine-induced cognitive deficits poses
significant challenges (Dean et al., 2013), and concerns regarding the interpretation
of these discrepancies and their clinical significance have been raised (Hart et al.,
2012). The culmination of evidence acquired through various methodologies (e.g.,
preclinical, cross-sectional human, and brain imaging studies), however, supports
the assertion that methamphetamine abuse does indeed cause cognitive decline in
at least some individuals (i.e., individuals at the age of early-to-middle adulthood),
and that individual difference factors such as education level and genotype further
moderate this relationship (Dean et al., 2013). Cognitive domains including episodic
memory, complex information processing speed, executive functions (e.g., response
inhibition, novel problem solving), and psychomotor functions appear to be most af-
fected in individuals with methamphetamine use disorders, with smaller, yet signif-
icant, effects also observed on measures of attention/working memory, language, and
visuoconstruction (Scott et al., 2007).
A number of these cognitive discrepancies and other behavioral changes associ-
ated with methamphetamine abuse have been related to methamphetamine-induced
alterations in neurotransmission, such as memory deficits and impaired psychomotor

coordination associated with reduced DAT site density (Volkow et al., 2001c), and
increased aggression associated with reduced SERT density (Sekine et al., 2006).
Further, preclinical evidence suggests D2-specific alterations of the dopaminergic
system may subserve some of the disturbances in learning observed with repeated
methamphetamine use. Specifically, using a reversal learning task and PET in a pre-
clinical sample of vervet monkeys given a chronic, escalating-dose regimen of meth-
amphetamine revealed associations between the change in response to positive
feedback and individual differences in the change in dopamine D2-like receptor
availability in the striatum, assessed pre- and postmethamphetamine regimen
(Groman et al., 2012).
Functional neuroimaging procedures have begun to identify region-specific alter-
ations in glucose metabolism and blood-oxygen-level-dependent measures of brain
activation associated with these potentially affected cognitive processes. For exam-
ple, glucose metabolism in the anterior and middle cingulate gyrus and the insula
was negatively correlated with error rates on an auditory vigilance task indexing
attentional processing in recently abstinent (4–7 days) methamphetamine abusers
(London et al., 2005). Evidence also suggests frontal and insular involvement in
learning and cognitive control changes associated with methamphetamine abuse.
On a color-word Stroop task administered during functional magnetic resonance im-
aging, methamphetamine abusers display reduced reaction time (RT) adjustments
and reduced PFC activity following conflict (i.e., incongruent) trials (Salo et al.,
2009, 2013), and reduced RT, increased error rate, and reduced activation of the right
inferior frontal gyrus (IFG), supplementary motor cortex/anterior cingulate gyrus,
and the anterior insular cortex during the incongruent condition (Nestor et al., 2011).
Region-specific alterations in brain activation have also been observed on decision-
making tasks in methamphetamine abusers. Methamphetamine abusers displayed re-
duced activation in the right IFG and the left medial frontal gyrus during a two-choice
prediction task (where only 50% of the responses are reinforced with a correct response
outcome), and a decrease in dorsolateral PFC (dlPFC) and right orbitofrontal cortex
(OFC) activity in the active compared to control conditions, as opposed to the increase
of activation in these areas observed in the healthy controls (Paulus et al., 2002). In a
follow-up study using the same task, recently abstinent (average 25 days) individuals
with methamphetamine dependence displayed reduced activation of the OFC, dlPFC,
anterior cingulate cortex (ACC), and parietal cortex irrespective of the outcome, and
attenuation of specific “success-related” patterns of brain activation as compared to
healthy controls (Paulus et al., 2003). Furthermore, the degree of activation in the right
middle frontal gyrus, middle temporal gyrus, and posterior cingulate during the two-
choice prediction task in early remission (3–4 weeks abstinent) was predictive of re-
lapse during a 1-year follow-up (Paulus et al., 2005).
On a temporal discounting task indexing reward-related decision-making, con-
trasting “hard choices,” where roughly equivalent preference is obtained for the im-
mediate and delayed reward choices, and “easy choices,” in which the choices differ
dramatically in value and preference, revealed less activation in the precuneus, right
4 Treatment 301
caudate nucleus, ACC, and dlPFC in recently abstinent (2–8 weeks) individuals with
methamphetamine dependence (Hoffman et al., 2008), and less activation of the left
dlPFC and right intraparietal sulcus in active methamphetamine abusers
(Monterosso et al., 2007), as compared to healthy controls. Furthermore,
methamphetamine-dependent individuals undergoing treatment display disrupted
risk-related processing, a component of decision-making, on the Risky Gains Task
in both the ACC and insula (Gowin et al., 2013).
In summary, ATS abuse is associated with specific task-related behavioral and
neural processing differences across a number of cognitive domains, which appear
to be moderated by dose, route of administration, and other individual difference var-
iables. Importantly, evidence is accumulating to suggest some of these differences
are associated with altered dopaminergic processing (Groman et al., 2012) and clin-
ically meaningful outcomes (Paulus et al., 2005), suggestive of a functional role for
these cognitive differences in the development and maintenance of methamphet-
amine addiction.
4 TREATMENT
At present, few effective options exist for individuals seeking treatment for ATS use
disorders, and to date, these options have been limited to psychosocial interventions.
A systematic review of cognitive and behavioral treatments as applied specifically to
methamphetamine use disorders concluded that good clinical outcomes are achieved
with cognitive behavioral treatment (CBT; with and without motivational interview-
ing [MI]) and contingency management (CM) therapies involving the systematic use
of reinforcement (Lee and Rawson, 2008). A number of caveats must be considered
when interpreting these conclusions, however, such as the durability of treatment ef-
fects (especially with respect to CM programs). Furthermore, the effectiveness of
psychosocial interventions is compromised by poor rates of treatment induction
and retention (Shearer, 2007), and methamphetamine-related cognitive deficits in
executive functioning, particularly those related to inhibitory control, have been hy-
pothesized to potentially render heavily cognitive-based treatments ineffective
(Baicy and London, 2007).
Given these important caveats of psychosocial interventions, and the heavy focus
on the neurobiology of methamphetamine dependence, attention has shifted to the
development of efficacious pharmacotherapies for methamphetamine addiction
(NIDA, 2005). At present, no medication is approved by the U.S. Food and Drug
Administration (FDA) for use in ATS use disorders. Numerous classes of medica-
tions are currently under study for methamphetamine use disorders, primarily in
small clinical trials (for a recent focused review, see Brensilver et al., 2013). Some
of the most promising medications include bupropion, mirtazapine, topiramate,
modafinil, and naltrexone.
Bupropion, commonly prescribed as an antidepressant or smoking-cessation
agent, is known to affect several biological targets. Widely described as a dopamine
and norepinephrine reuptake inhibitor (Stahl et al., 2004), bupropion also acts as a
noncompetitive antagonist of several neuronal nicotinic acetylcholine (nACh) recep-
tors (Slemmer et al., 2000). Clinical use of bupropion has been associated with re-
duced use of methamphetamine among baseline light, but not heavy,
methamphetamine users (identified in a post hoc analysis; Shoptaw et al., 2008);
however, its precise mechanism of action remains unclear.
In a 12-week trial, mirtazapine, a noradrenergic and specific serotonergic antide-
pressant, combined with CBT/MI counseling has also been associated with signifi-
cant reductions in methamphetamine use (percent positive urines at the week
12 visit) in a sample of methamphetamine-dependent men who have sex with
men (Colfax et al., 2011). The clinical efficacy of this agent may be related to its
ability to enhance of the release of norepinephrine and 5-HT1A-mediated serotoner-
gic transmission (Anttila and Leinonen, 2001).
Topiramate, a sulfamate fructopyranose derivative and anticonvulsant, has been
associated with reductions in methamphetamine use in large multisite clinical trial;
however, no effects on total abstinence (negative urines during 6–12-week follow-
up) were observed (Elkashef et al., 2012). Further analysis of this data identified a
small subgroup of patients who exhibited consistent reductions of use or achieved
abstinence during follow-up which were associated with topiramate treatment. This
subgroup consisted of individuals who were more likely to have discontinued meth-
amphetamine use (i.e., have a negative last urine) during the week prior to random-
ization (Ma et al., 2013) suggesting that topiramate may function best for relapse
prevention. GABAergic modulation may be one possible mechanism underlying
the potential efficacy of topiramate for methamphetamine treatment. Topiramate
is known to facilitate GABAergic function via enhancement of inhibitory
GABAA-mediated currents at nonbenzodiazepine sites on the GABAA receptor
(White et al., 2000). Topiramate also antagonizes glutaminergic activity through
an effect at kainate/alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid re-
ceptors (Gryder and Rogawski, 2003). Through these processes, topiramate is
thought to modulate cortico-mesolimbic dopaminergic activity ( Johnson, 2004), po-
tentially stabilizing this activity and subsequently helping to prevent relapse or re-
duce methamphetamine use.
Cognitive-enhancing medications such as modafinil, an analeptic drug with
known cognitive-enhancing properties, have garnered recent attention given the
known cognitive deficits associated with chronic methamphetamine use (e.g.,
Ghahremani et al., 2011). Modafinil combined with CBT was associated with re-
duced methamphetamine use within a small sample of HIV + gay men dependent
on methamphetamine (McElhiney et al., 2009), although recent trials have not found
strong support for a direct effect of modafinil on abstinence outcomes (e.g.,
Anderson et al., 2012; Heinzerling et al., 2010). The mechanism of action of mod-
afinil is complex, involving multiple neurotransmitter systems, but its potential ef-
fects on ATS use may be related to inhibition of catecholamine transporters (Madras
et al., 2006; Volkow et al., 2009), thereby increasing extracellular dopamine and nor-
epinephrine levels.
Lastly, naltrexone, an opioid antagonist with greatest affinity for the m- and
k-opioid receptors in humans (Emmerson et al., 1994; Toll et al., 1998), has been
associated with reduced amphetamine use and greater abstinence rates in a sample
of amphetamine-dependent individuals ( Jayaram-Lindstrom et al., 2008). Further,
amphetamine dependent patients with high levels of naltrexone ( 2 ng/ml) in their
blood were 2.27 times more likely to be abstinent than patients with low naltrexone
blood levels (<2 ng/ml; Grant et al., 2010). Naltrexone-related reductions of cue-
induced craving and subjective responses to methamphetamine administration have
recently been observed in nontreatment seeking individuals with methamphetamine
use disorders (Ray et al., 2015), advancing naltrexone as a potential treatment for
methamphetamine addiction as well. The blockage of ATS-induced dopamine re-
lease in the mesolimbic dopamine system has been proposed as the neural mecha-
nism underlying naltrexone’s effects on craving and subjective reward
(Ashenhurst et al., 2012; Benjamin et al., 1993; Jayaram-Lindstrom et al., 2004;
Lee et al., 2005; Naleid et al., 2005; Widdowson and Holman, 1992) which may un-
derlie the observed attenuation of ATS use.
In summary, the clinically limiting caveats of psychosocial treatments have en-
gendered a strong interest in medication development for the treatment of ATS use
disorders. A number of medications are currently under study in clinical research for
the treatment of ATS use disorders, many with promising preliminary results. Pre-
clinical research is also continuously advancing novel pharmacological agents that
may progress to human trials for ATS use disorders. For example, oxytocin, a mam-
malian neuropeptide, has shown promise in reducing responding for intravenous
methamphetamine in rodent models (Carson et al., 2010; Cox et al., 2013), which
may one day translate to improved clinical outcomes associated with oxytocin
treatment in humans. Treatment development for ATS use disorders has been a
challenging enterprise, yet consistent with the addiction field broadly (Litten
et al., 2012), efforts to refocus the field toward medications with novel therapeutic
targets (e.g., the opioidergic system, cognitive enhancement) hold considerable
promise for these complex disorders.

Illicit ATS use continues to be highly prevalent despite numerous attempts to limit
public access to the drugs and their precursors. Methamphetamine in particular is the
most frequently used ATS worldwide and has the highest abuse potential, yet the
diversion of stimulant medications is also a growing concern. Through actions on
the brain’s major dopaminergic, noradrenergic, serotonergic, and opioidergic path-
ways, repeated use of ATS (especially methamphetamine) is associated with signif-
icant neurotoxic effects and neurocognitive deficits, with only a few of such effects
known to remediate following sustained abstinence. Thus, early identification of
problematic ATS use and effective treatment implementation is critical to successful
outcomes.
Advances in the identification of the neural pathways affected by ATS use have
begun to highlight potential targets for intervention. The development of efficacious
pharmacologic interventions is most promising in this regard, particularly given the
profound neurochemical alterations associated with ATS use. Medications that act
on the dopaminergic, GABAergic, and serotonergic systems have shown promise
in reducing ATS use in clinical samples, and increasing evidence for the opioidergic
system’s role in the development of ATS use disorders has advanced pharmacologic
agents targeting this pathway as plausible treatments.
By integrating basic neuroscience into treatment development research, one may
elucidate how psychosocial and pharmacological interventions function to reduce
ATS use and for whom specific interventions may be most efficacious. For example,
the most effective medications may function via novel mechanisms such as enhanc-
ing the effectiveness of existent psychosocial interventions (e.g., via decreasing cog-
nitive impairment) and by targeting intermediate phenotypes of addiction (e.g.,
relapse prevention/craving) (NIDA, 2005). Further, current research suggests that
clinical outcomes may be improved by tailoring interventions to differences in pa-
tient presentation (e.g., heaviness of use, age of user, cognitive capability), some of
which effects may be driven by individual differences in dopaminergic processing.
Clinical neuroscience research is well positioned to address these questions and ul-
timately provide relief to thousands of individuals currently struggling to overcome
their addiction to these stimulating and reinforcing drugs.
REFERENCES
ders. American Psychiatric Association, Washington, DC.
Anderson, A.L., Li, S.H., Biswas, K., Mcsherry, F., Holmes, T., Iturriaga, E., Kahn, R.,
Chiang, N., Beresford, T., Campbell, J., Haning, W., Mawhinney, J., Mccann, M.,
Rawson, R., Stock, C., Weis, D., Yu, E., Elkashef, A.M., 2012. Modafinil for the treatment
of methamphetamine dependence. Drug Alcohol Depend. 120, 135–141.
Anglin, M.D., Burke, C., Perrochet, B., Stamper, E., Dawud-Noursi, S., 2000. History of the
methamphetamine problem. J. Psychoactive Drugs 32, 137–141.
Anttila, S.A., Leinonen, E.V., 2001. A review of the pharmacological and clinical profile of
mirtazapine. CNS Drug Rev. 7, 249–264.
Ashenhurst, J.R., Bujarski, S., Ray, L.A., 2012. Delta and kappa opioid receptor polymor-
phisms influence the effects of naltrexone on subjective responses to alcohol. Pharmacol.
Baicy, K., London, E.D., 2007. Corticolimbic dysregulation and chronic methamphetamine
abuse. Addiction 102 (Suppl. 1), 5–15.
Benjamin, D., Grant, E.R., Pohorecky, L.A., 1993. Naltrexone reverses ethanol-induced do-
pamine release in the nucleus accumbens in awake, freely moving rats. Brain Res.
621, 137–140.
Berman, S., O’neill, J., Fears, S., Bartzokis, G., London, E.D., 2008. Abuse of amphetamines
and structural abnormalities in the brain. Ann. N. Y. Acad. Sci. 1141, 195–220.
References 305
Berridge, C.W., Waterhouse, B.D., 2003. The locus coeruleus-noradrenergic system: modu-
lation of behavioral state and state-dependent cognitive processes. Brain Res. Brain Res.
Rev. 42, 33–84.
Bonci, A., Williams, J.T., 1997. Increased probability of GABA release during withdrawal
from morphine. J. Neurosci. 17, 796–803.
Boutrel, B., 2008. A neuropeptide-centric view of psychostimulant addiction. Br. J. Pharma-
col. 154, 343–357.
Brensilver, M., Heinzerling, K.G., Shoptaw, S., 2013. Pharmacotherapy of amphetamine-type
stimulant dependence: an update. Drug Alcohol Rev. 32, 449–460.
Bustamante, D., You, Z.B., Castel, M.N., Johansson, S., Goiny, M., Terenius, L., Hokfelt, T.,
Herrera-Marschitz, M., 2002. Effect of single and repeated methamphetamine treatment
on neurotransmitter release in substantia nigra and neostriatum of the rat.
J. Neurochem. 83, 645–654.
Carson, D.S., Cornish, J.L., Guastella, A.J., Hunt, G.E., Mcgregor, I.S., 2010. Oxytocin de-
creases methamphetamine self-administration, methamphetamine hyperactivity, and re-
lapse to methamphetamine-seeking behaviour in rats. Neuropharmacology 58, 38–43.
Chang, L., Alicata, D., Ernst, T., Volkow, N., 2007. Structural and metabolic brain changes in
the striatum associated with methamphetamine abuse. Addiction 102 (Suppl. 1), 16–32.
Chiu, C.T., Ma, T., Ho, I.K., 2006. Methamphetamine-induced behavioral sensitization in
mice: alterations in mu-opioid receptor. J. Biomed. Sci. 13, 797–811.
Cho, A.K., Melega, W.P., 2002. Patterns of methamphetamine abuse and their consequences.
J. Addict. Dis. 21, 21–34.
Colfax, G.N., Santos, G.M., Das, M., Santos, D.M., Matheson, T., Gasper, J., Shoptaw, S.,
Vittinghoff, E., 2011. Mirtazapine to reduce methamphetamine use: a randomized con-
trolled trial. Arch. Gen. Psychiatry 68, 1168–1175.
Cox, B.M., Young, A.B., See, R.E., Reichel, C.M., 2013. Sex differences in methamphetamine
seeking in rats: impact of oxytocin. Psychoneuroendocrinology 38, 2343–2353.
Cruickshank, C.C., Dyer, K.R., 2009. A review of the clinical pharmacology of methamphet-
amine. Addiction 104, 1085–1099.
Dean, A.C., Groman, S.M., Morales, A.M., London, E.D., 2013. An evaluation of the
evidence that methamphetamine abuse causes cognitive decline in humans. Neuro-
psychopharmacology 38, 259–274.
Elkashef, A., Kahn, R., Yu, E., Iturriaga, E., Li, S.H., Anderson, A., Chiang, N., Ait-Daoud, N.,
Weiss, D., Mcsherry, F., Serpi, T., Rawson, R., Hrymoc, M., Weis, D., Mccann, M.,
Pham, T., Stock, C., Dickinson, R., Campbell, J., Gorodetzky, C., Haning, W.,
Carlton, B., Mawhinney, J., Li, M.D., Johnson, B.A., 2012. Topiramate for the treatment
of methamphetamine addiction: a multi-center placebo-controlled trial. Addiction
107, 1297–1306.
Emmerson, P.J., Liu, M.R., Woods, J.H., Medzihradsky, F., 1994. Binding affinity and selec-
tivity of opioids at mu, delta and kappa receptors in monkey brain membranes.
Ernst, T., Chang, L., Leonido-Yee, M., Speck, O., 2000. Evidence for long-term neurotoxicity
associated with methamphetamine abuse: a 1H MRS study. Neurology 54, 1344–1349.
Ford, C.P., Mark, G.P., Williams, J.T., 2006. Properties and opioid inhibition of mesolimbic
dopamine neurons vary according to target location. J. Neurosci. 26, 2788–2797.
Ghahremani, D.G., Tabibnia, G., Monterosso, J., Hellemann, G., Poldrack, R.A.,
London, E.D., 2011. Effect of modafinil on learning and task-related brain activity
in methamphetamine-dependent and healthy individuals. Neuropsychopharmacology

36, 950–959.
Gonzales, R., Mooney, L., Rawson, R.A., 2010. The methamphetamine problem in the United
States. Annu. Rev. Public Health 31, 385–398.
Gowin, J.L., Stewart, J.L., May, A.C., Ball, T.M., Wittmann, M., Tapert, S.F., Paulus, M.P.,
2013. Altered cingulate and insular cortex activation during risk-taking in methamphet-
amine dependence: losses lose impact. Addiction 109, 237–247.
Grant, J.E., Odlaug, B.L., Kim, S.W., 2010. A double-blind, placebo-controlled study of
N-acetyl cysteine plus naltrexone for methamphetamine dependence. Eur. Neuropsycho-
pharmacol. 20, 823–828.
Groman, S.M., Lee, B., Seu, E., James, A.S., Feiler, K., Mandelkern, M.A., London, E.D.,
Jentsch, J.D., 2012. Dysregulation of D(2)-mediated dopamine transmission in monkeys
after chronic escalating methamphetamine exposure. J. Neurosci. 32, 5843–5852.
Gryder, D.S., Rogawski, M.A., 2003. Selective antagonism of GluR5 kainate-receptor-medi-
ated synaptic currents by topiramate in rat basolateral amygdala neurons. J. Neurosci.
23, 7069–7074.
Hanson, G.R., Merchant, K.M., Letter, A.A., Bush, L., Gibb, J.W., 1988. Characterization of
methamphetamine effects on the striatal-nigral dynorphin system. Eur. J. Pharmacol.
155, 11–18.
Hart, C.L., Marvin, C.B., Silver, R., Smith, E.E., 2012. Is cognitive functioning impaired in
methamphetamine users? A critical review. Neuropsychopharmacology 37, 586–608.
Heinzerling, K.G., Swanson, A.N., Kim, S., Cederblom, L., Moe, A., Ling, W., Shoptaw, S.,
2010. Randomized, double-blind, placebo-controlled trial of modafinil for the treatment of
methamphetamine dependence. Drug Alcohol Depend. 109, 20–29.
Hirose, N., Murakawa, K., Takada, K., Oi, Y., Suzuki, T., Nagase, H., Cools, A.R.,
Koshikawa, N., 2005. Interactions among mu- and delta-opioid receptors, especially pu-
tative delta1- and delta2-opioid receptors, promote dopamine release in the nucleus
accumbens. Neuroscience 135, 213–225.
Hoffman, W.F., Schwartz, D.L., Huckans, M.S., Mcfarland, B.H., Meiri, G., Stevens, A.A.,
Mitchell, S.H., 2008. Cortical activation during delay discounting in abstinent metham-
phetamine dependent individuals. Psychopharmacology 201, 183–193.
Homer, B.D., Solomon, T.M., Moeller, R.W., Mascia, A., Deraleau, L., Halkitis, P.N., 2008.
Methamphetamine abuse and impairment of social functioning: a review of the
underlying neurophysiological causes and behavioral implications. Psychol. Bull.
134, 301–310.
Hornung, J.P., 2003. The human raphe nuclei and the serotonergic system. J. Chem. Neuroa-
nat. 26, 331–343.
Hurd, Y.L., Herkenham, M., 1992. Influence of a single injection of cocaine, amphetamine or
GBR 12909 on mRNA expression of striatal neuropeptides. Brain Res. Mol. Brain Res.
16, 97–104.
Itzhak, Y., Ali, S.F., 2002. Behavioral consequences of methamphetamine-induced neurotox-
icity in mice: relevance to the psychopathology of methamphetamine addiction. Ann. N.
Y. Acad. Sci. 965, 127–135.
Jayaram-Lindstrom, N., Wennberg, P., Hurd, Y.L., Franck, J., 2004. Effects of naltrexone on
the subjective response to amphetamine in healthy volunteers. J. Clin. Psychopharmacol.
24, 665–669.
Jayaram-Lindstrom, N., Hammarberg, A., Beck, O., Franck, J., 2008. Naltrexone for the
treatment of amphetamine dependence: a randomized, placebo-controlled trial. Am. J.
Psychiatry 165, 1442–1448.
References 307
Johanson, C.E., Frey, K.A., Lundahl, L.H., Keenan, P., Lockhart, N., Roll, J., Galloway, G.P.,
Koeppe, R.A., Kilbourn, M.R., Robbins, T., Schuster, C.R., 2006. Cognitive function and
nigrostriatal markers in abstinent methamphetamine abusers. Psychopharmacology
185, 327–338.
Johnson, B.A., 2004. Topiramate-induced neuromodulation of cortico-mesolimbic dopamine
function: a new vista for the treatment of comorbid alcohol and nicotine dependence? Ad-
dict. Behav. 29, 1465–1479.
Lee, N.K., Rawson, R.A., 2008. A systematic review of cognitive and behavioural therapies
for methamphetamine dependence. Drug Alcohol Rev. 27, 309–317.
Lee, Y.K., Park, S.W., Kim, Y.K., Kim, D.J., Jeong, J., Myrick, H., Kim, Y.H., 2005. Effects of
naltrexone on the ethanol-induced changes in the rat central dopaminergic system. Alcohol
Alcohol. 40, 297–301.
Litten, R.Z., Egli, M., Heilig, M., Cui, C., Fertig, J.B., Ryan, M.L., Falk, D.E., Moss, H.,
Huebner, R., Noronha, A., 2012. Medications development to treat alcohol dependence:
a vision for the next decade. Addict. Biol. 17, 513–527.
London, E.D., Berman, S.M., Voytek, B., Simon, S.L., Mandelkern, M.A., Monterosso, J.,
Thompson, P.M., Brody, A.L., Geaga, J.A., Hong, M.S., Hayashi, K.M., Rawson, R.A.,
Ling, W., 2005. Cerebral metabolic dysfunction and impaired vigilance in recently absti-
nent methamphetamine abusers. Biol Psychiatry 58, 770–778.
Ma, J.Z., Johnson, B.A., Yu, E., Weiss, D., Mcsherry, F., Saadvandi, J., Iturriaga, E., Ait-Daoud,
N., Rawson, R.A., Hrymoc, M., Campbell, J., Gorodetzky, C., Haning, W., Carlton, B.,
Mawhinney, J., Weis, D., Mccann, M., Pham, T., Stock, C., Dickinson, R., Elkashef, A.,
Li, M.D., 2013. Fine-grain analysis of the treatment effect of topiramate on methamphet-
amine addiction with latent variable analysis. Drug Alcohol Depend. 130, 45–51.
Madras, B.K., Xie, Z., Lin, Z., Jassen, A., Panas, H., Lynch, L., Johnson, R., Livni, E.,
Spencer, T.J., Bonab, A.A., Miller, G.M., Fischman, A.J., 2006. Modafinil occupies do-
pamine and norepinephrine transporters in vivo and modulates the transporters and trace
amine activity in vitro. J. Pharmacol. Exp. Ther. 319, 561–569.
Mansour, A., Fox, C.A., Akil, H., Watson, S.J., 1995. Opioid-receptor mRNA expression in
the rat CNS: anatomical and functional implications. Trends Neurosci. 18, 22–29.
Mccann, U.D., Wong, D.F., Yokoi, F., Villemagne, V., Dannals, R.F., Ricaurte, G.A., 1998.
Reduced striatal dopamine transporter density in abstinent methamphetamine and meth-
cathinone users: evidence from positron emission tomography studies with [11C]WIN-
35,428. J. Neurosci. 18, 8417–8422.
Mcelhiney, M.C., Rabkin, J.G., Rabkin, R., Nunes, E.V., 2009. Provigil (modafinil) plus cog-
nitive behavioral therapy for methamphetamine use in HIV + gay men: a pilot study. Am. J.
Drug Alcohol Abuse 35, 34–37.
Melega, W.P., Williams, A.E., Schmitz, D.A., Distefano, E.W., Cho, A.K., 1995. Pharmaco-
kinetic and pharmacodynamic analysis of the actions of D-amphetamine and
D-methamphetamine on the dopamine terminal. J. Pharmacol. Exp. Ther. 274, 90–96.
Monterosso, J.R., Ainslie, G., Xu, J., Cordova, X., Domier, C.P., London, E.D., 2007. Fron-
toparietal cortical activity of methamphetamine-dependent and comparison subjects per-
forming a delay discounting task. Hum. Brain Mapp. 28, 383–393.
Murakawa, K., Hirose, N., Takada, K., Suzuki, T., Nagase, H., Cools, A.R., Koshikawa, N.,
2004. Deltorphin II enhances extracellular levels of dopamine in the nucleus accumbens
via opioid receptor-independent mechanisms. Eur. J. Pharmacol. 491, 31–36.
Naleid, A.M., Grace, M.K., Cummings, D.E., Levine, A.S., 2005. Ghrelin induces feeding in
the mesolimbic reward pathway between the ventral tegmental area and the nucleus
accumbens. Peptides 26, 2274–2279.
National Institute on Drug Abuse (Nida), 2005. Medications Development Research for Treat-
ment of Amphetamine and Methamphetamine Addiction. U.S. Department of Health and
Human Services, National Institutes of Health, Bethesda, MD.
Nestor, L.J., Ghahremani, D.G., Monterosso, J., London, E.D., 2011. Prefrontal hypoactiva-
tion during cognitive control in early abstinent methamphetamine-dependent subjects.
Psychiatry Res. 194, 287–295.
Olive, M.F., Koenig, H.N., Nannini, M.A., Hodge, C.W., 2001. Stimulation of endorphin neu-
rotransmission in the nucleus accumbens by ethanol, cocaine, and amphetamine.
J. Neurosci. 21, RC184.
Paulus, M.P., Hozack, N.E., Zauscher, B.E., Frank, L., Brown, G.G., Braff, D.L., Schuckit, M.A.,
2002. Behavioral and functional neuroimaging evidence for prefrontal dysfunction in
methamphetamine-dependent subjects. Neuropsychopharmacology 26, 53–63.
Paulus, M.P., Hozack, N., Frank, L., Brown, G.G., Schuckit, M.A., 2003. Decision making by
methamphetamine-dependent subjects is associated with error-rate-independent decrease
in prefrontal and parietal activation. Biol. Psychiatry 53, 65–74.
Gen. Psychiatry 62, 761–768.
Rabiner, D.L., 2013. Stimulant prescription cautions: addressing misuse, diversion and malin-
gering. Curr. Psychiatry Rep. 15, 375.
Ray, L.A., Bujarski, S., Courtney, K.E., Moallem, N.R., Lunny, K., Roche, D., Leventhal, A.M.,
Shoptaw, S., Heinzerling, K., London, E.D., Miotto, K., 2015. The Effects of Naltrexone on
Subjective Response to Methamphetamine in a Clinical Sample: a Double-Blind, Placebo-
Controlled Laboratory Study. Neuropsychopharmacology, epub ahead of print.
Ricaurte, G.A., Mechan, A.O., Yuan, J., Hatzidimitriou, G., Xie, T., Mayne, A.H., Mccann, U.D.,
2005. Amphetamine treatment similar to that used in the treatment of adult attention-
deficit/hyperactivity disorder damages dopaminergic nerve endings in the striatum of adult
nonhuman primates. J. Pharmacol. Exp. Ther. 315, 91–98.
Salo, R., Ursu, S., Buonocore, M.H., Leamon, M.H., Carter, C., 2009. Impaired prefrontal cor-
tical function and disrupted adaptive cognitive control in methamphetamine abusers: a
functional magnetic resonance imaging study. Biol. Psychiatry 65, 706–709.
Salo, R., Fassbender, C., Buonocore, M.H., Ursu, S., 2013. Behavioral regulation in metham-
phetamine abusers: an fMRI study. Psychiatry Res. 211, 234–238.
Schouw, M.L., Caan, M.W., Geurts, H.M., Schmand, B., Booij, J., Nederveen, A.J.,
Reneman, L., 2013. Monoaminergic dysfunction in recreational users of dexamphetamine.
Eur. Neuropsychopharmacol. 23, 1491–1502.
Scott, J.C., Woods, S.P., Matt, G.E., Meyer, R.A., Heaton, R.K., Atkinson, J.H., Grant, I.,
2007. Neurocognitive effects of methamphetamine: a critical review and meta-analysis.
Neuropsychol. Rev. 17, 275–297.
Sekine, Y., Ouchi, Y., Takei, N., Yoshikawa, E., Nakamura, K., Futatsubashi, M., Okada, H.,
Minabe, Y., Suzuki, K., Iwata, Y., Tsuchiya, K.J., Tsukada, H., Iyo, M., Mori, N., 2006.
Brain serotonin transporter density and aggression in abstinent methamphetamine abusers.
Arch. Gen. Psychiatry 63, 90–100.
Shearer, J., 2007. Psychosocial approaches to psychostimulant dependence: a systematic re-
view. J. Subst. Abus. Treat. 32, 41–52.
Shoblock, J.R., Maisonneuve, I.M., Glick, S.D., 2003a. Differences between
d-methamphetamine and d-amphetamine in rats: working memory, tolerance, and extinc-
tion. Psychopharmacology 170, 150–156.
References 309
Shoblock, J.R., Sullivan, E.B., Maisonneuve, I.M., Glick, S.D., 2003b. Neurochemical and
behavioral differences between d-methamphetamine and d-amphetamine in rats.
Psychopharmacology 165, 359–369.
Shoji, Y., Delfs, J., Williams, J.T., 1999. Presynaptic inhibition of GABA(B)-mediated syn-
aptic potentials in the ventral tegmental area during morphine withdrawal. J. Neurosci.
19, 2347–2355.
Shoptaw, S., Heinzerling, K.G., Rotheram-Fuller, E., Steward, T., Wang, J., Swanson, A.N.,
De La Garza, R., Newton, T., Ling, W., 2008. Randomized, placebo-controlled trial of
bupropion for the treatment of methamphetamine dependence. Drug Alcohol Depend.
96, 222–232.
Slemmer, J.E., Martin, B.R., Damaj, M.I., 2000. Bupropion is a nicotinic antagonist.
Smith, A.J., Mcginty, J.F., 1994. Acute amphetamine or methamphetamine alters opioid pep-
tide mRNA expression in rat striatum. Brain Res. Mol. Brain Res. 21, 359–362.
Stahl, S.M., Pradko, J.F., Haight, B.R., Modell, J.G., Rockett, C.B., Learned-Coughlin, S.,
2004. A review of the neuropharmacology of bupropion, a dual norepinephrine and dopa-
mine reuptake inhibitor. Prim Care Companion J. Clin. Psychiatry 6, 159–166.
Substance Abuse and Mental Health Services Administration (SAMHSA), 2013. Results from
the 2012 National Survey on Drug Use and Health: Summary of National Findings.
Substance Abuse and Mental Health Services Administration, Rockville, MD. NSDUH
Series H-46, HHS Publication No. (SMA) 13–4795.
Substance Abuse and Mental Health Services Administration (SAMHSA), Center for Behav-
ioral Health Statistics and Quality, 2013b. Treatment Episode Data Set (TEDS):
2001–2011. National Admissions to Substance Abuse Treatment Services. Substance
Abuse and Mental Health Services Administration, Rockville, MD.
Sulzer, D., Sonders, M.S., Poulsen, N.W., Galli, A., 2005. Mechanisms of neurotransmitter
release by amphetamines: a review. Prog. Neurobiol. 75, 406–433.
Toll, L., Berzetei-Gurske, I.P., Polgar, W.E., Brandt, S.R., Adapa, I.D., Rodriguez, L.,
Schwartz, R.W., Haggart, D., O’brien, A., White, A., Kennedy, J.M., Craymer, K.,
Farrington, L., Auh, J.S., 1998. Standard binding and functional assays related to medica-
tions development division testing for potential cocaine and opiate narcotic treatment
medications. NIDA Res. Monogr. 178, 440–466.
Trigo, J.M., Martin-Garcı́a, E., Berrendero, F., Robledo, P., Maldonado, R., 2010. The endog-
enous opioid system: a common substrate in drug addiction. Drug Alcohol Depend.
108, 183–194.
United Nations Office on Drugs and Crime (UNODC), 2012. World Drug Report 2012.
United Nations publication, Sales No. E.12.XI.1. United Nations Office on Drugs and
Crime, Vienna.
United Nations Office on Drugs and Crime (UNODC), 2013. World Drug Report 2013. United
Nations publication, Sales No. E.13.XI.6. United Nations Office on Drugs and Crime,
Vienna.
Villemagne, V., Yuan, J., Wong, D.F., Dannals, R.F., Hatzidimitriou, G., Mathews, W.B.,
Ravert, H.T., Musachio, J., Mccann, U.D., Ricaurte, G.A., 1998. Brain dopamine
neurotoxicity in baboons treated with doses of methamphetamine comparable to
those recreationally abused by humans: evidence from [11C]WIN-35,428 positron emis-
sion tomography studies and direct in vitro determinations. J. Neurosci. 18, 419–427.
Volkow, N.D., Chang, L., Wang, G.J., Fowler, J.S., Ding, Y.S., Sedler, M., Logan, J.,
Franceschi, D., Gatley, J., Hitzemann, R., Gifford, A., Wong, C., Pappas, N., 2001a.
Low level of brain dopamine D2 receptors in methamphetamine abusers: association with

metabolism in the orbitofrontal cortex. Am. J. Psychiatry 158, 2015–2021.
Volkow, N.D., Chang, L., Wang, G.J., Fowler, J.S., Franceschi, D., Sedler, M., Gatley, S.J.,
Miller, E., Hitzemann, R., Ding, Y.S., Logan, J., 2001b. Loss of dopamine transporters
in methamphetamine abusers recovers with protracted abstinence. J. Neurosci.
21, 9414–9418.
Volkow, N.D., Chang, L., Wang, G.J., Fowler, J.S., Leonido-Yee, M., Franceschi, D.,
Sedler, M.J., Gatley, S.J., Hitzemann, R., Ding, Y.S., Logan, J., Wong, C., Miller, E.N.,
2001c. Association of dopamine transporter reduction with psychomotor impairment in
methamphetamine abusers. Am. J. Psychiatry 158, 377–382.
Volkow, N.D., Fowler, J.S., Logan, J., Alexoff, D., Zhu, W., Telang, F., Wang, G.J., Jayne, M.,
Hooker, J.M., Wong, C., Hubbard, B., Carter, P., Warner, D., King, P., Shea, C., Xu, Y.,
Muench, L., Apelskog-Torres, K., 2009. Effects of modafinil on dopamine and dopamine
transporters in the male human brain: clinical implications. J. Am. Med. Assoc.
301, 1148–1154.
Wang, J.Q., Mcginty, J.F., 1995. Dose-dependent alteration in zif/268 and preprodynorphin
mRNA expression induced by amphetamine or methamphetamine in rat forebrain.
White, H.S., Brown, S.D., Woodhead, J.H., Skeen, G.A., Wolf, H.H., 2000. Topiramate mod-
ulates GABA-evoked currents in murine cortical neurons by a nonbenzodiazepine mech-
anism. Epilepsia 41 (Suppl. 1), S17–S20.
Widdowson, P.S., Holman, R.B., 1992. Ethanol-induced increase in endogenous dopamine
release may involve endogenous opiates. J. Neurochem. 59, 157–163.
Wood, S., Sage, J.R., Shuman, T., Anagnostaras, S.G., 2014. Psychostimulants and cognition:
a continuum of behavioral and cognitive activation. Pharmacol. Rev. 66, 193–221.
CHAPTER
Behavioral addictions in
addiction medicine: from
mechanisms to practical
considerations
16
Barbara C. Banz*, Sarah W. Yip*, Yvonne H.C. Yau†,{, Marc N. Potenza*,},},1
*Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
†
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University,
Montre´al, QC, Canada
{
Montreal Neurological Institute, 3801 Rue University, Montre´al, QC, Canada
}
Department of Neurobiology, Child Study Center, and CASA Columbia, Yale University School of
Medicine, New Haven, CT, USA
}
Connecticut Mental Health Center, Yale University School of Medicine, New Haven, CT, USA
1
Corresponding author: Tel.: (203) 974-7356; Fax: (203) 974-7366,
Abstract
Recent progress has been made in our understanding of nonsubstance or “behavioral”
addictions, although these conditions and their most appropriate classification remain
debated and the knowledge basis for understanding the pathophysiology of and treatments
for these conditions includes important gaps. Recent developments include the classifica-
tion of gambling disorder as a “Substance-Related and Addictive Disorder” in the 5th
edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and
proposed diagnostic criteria for Internet Gaming Disorder in Section 3 of DSM-5. This
chapter reviews current neuroscientific understandings of behavioral addictions and the
potential of neurobiological data to assist in the development of improved policy, preven-
tion, and treatment efforts.
Keywords
Gambling disorder, Internet, Gaming, Addiction, Neuroscience, Treatment

311
312 CHAPTER 16 Behavioral addictions
1 INTRODUCTION
While debated, the concept of nonsubstance or “behavioral” addictions has gained
traction as evidenced by the recent classification of gambling disorder as a
“Substance-Related and Addictive Disorder” in the Diagnostic and Statistical Man-
ual of Mental Disorders (5th edition) (DSM-5) and definition in Section 3 of DSM-5
of diagnostic criteria for Internet gaming disorder (IGD) (American Psychiatric
Association, 2013; Petry and O’Brien, 2013). These classification and inclusion ef-
forts have been informed by neuroscientific data. A current challenge exists in trans-
lating a neuroscientific understanding of these disorders into more effective
treatments. Behaviors that may involve excessive or problematic engagement in-
clude gambling, Internet use, and gaming. The following chapter reviews the current
neurobiological understanding of, and discusses treatment implications with respect
to, excessive and interfering patterns of gambling, Internet use, and gaming.
2 GAMBLING DISORDER
The reclassification of gambling disorder in the DSM-5 was based upon evidence of
clinical, neurobiological, and other similarities between substance-use and gambling
disorders (Potenza, 2006). Due to the recent classification and renaming of
“pathological gambling” (PG) in DSM-IV-TR to “gambling disorder” in DSM-5
(American Psychiatric Association, 2000, 2013; Potenza, 2014), this condition will
be referred to as gambling disorder in this chapter despite a majority of data emanat-
ing from studies of PG.
3 NEURAL FEATURES OF GAMBLING DISORDER

Phenomenological similarities between substance-use and gambling disorders have
been observed, leading to inclusionary criteria addressing tolerance, withdrawal, and in-
terference in major areas of life functioning for these conditions. Recently, there have
been various other reviews of neural function in gambling disorder (Leeman and
Potenza, 2012, 2013; Meng et al., 2014). The current review will describe recent findings
related to processes which may be beneficial for advancing treatment of this disorder.
3.1 NEUROCOGNITIVE FACETS

Neurocognitive measures allow for evaluation of possible dysfunction in a variety
of cognitive facets and offer insight in to potential underlying neural regions of impor-
tance in behavioral addictions (Potenza, 2014). The evaluation of patterns of dysfunc-
tion allows for comparisons to healthy comparison subjects, across substance-use
disorders, and various other populations of interest which allow for a more in-depth
understanding of similarities and differences between these groups (Choi et al.,
2014; Leeman and Potenza, 2012; Noël et al., 2013; Yan et al., 2014). Importantly,
evaluation of neurocognitive function in PG through neurocognitive tasks has provided
insight into the maintenance of this disorder (for review, see Brevers et al., 2013;
3 Neural features of gambling disorder 313
van Holst et al., 2010). Together, these data inform potential approaches to the
identification of those at risk and the development of more effective treatments.
3.2 ELECTROPHYSIOLOGY
Electrophysiological studies involving electroencephalogram (EEG) data and tasks
designed to elicit event-related potentials (ERPs) offer insight into neural function
linked to sensory or cognitive processing. To date, these methods have not been ex-
tensively used within individuals with PG, with existing studies frequently using
gambling tasks, as described below.
Feedback-related negativity (FRN), an ERP component elicited through feedback
related to subject performance, has been evaluated. Healthy comparison subjects and
those with PG presented with similar FRN amplitudes in win and loss conditions;
however, in PG subjects, an additional FRN occurred earlier with latency and ampli-
tude correlated with severity of PG (Oberg et al., 2011). In PG, blunted P3 amplitude
and EEG power in theta-band activity were also found in response to high-risk scenar-
ios (Oberg et al., 2011). More recently, Lole and colleagues (2015) found attenuated
FRN and feedback-related positivity in response to losses and wins with no difference
in P3b amplitude in response to large and small rewards in PG. These data suggest
varied sensitivity to risk, reward, and loss in PG which can be evaluated through EEG.
During simulated blackjack, reward resulted in more positive reactivity in PG
compared to healthy comparison subjects during a window after the FRN (between
270 and 320 ms); a difference in positivity was found within PG subjects between re-
sponses to rewards and losses, with no differences in healthy comparison subjects
(Hewig et al., 2010). However, during varying loss conditions, PG subjects did not
show differences in reactivity during conditions of near or full losses during this same
window of activity, unlike healthy comparison subjects (Kreussel et al., 2013). When
comparing occasional gamblers and PG subjects during a blackjack task, reactivity in
these two groups differed in both low- and high-risk conditions during risk assessment,
and PG subjects presented with greater negativity during reward processing (Miedl
et al., 2014). Together, these studies differences in the electrophysiological brain cor-
relates of reward/loss processing and suggest a need for additional study of cue-related
craving effects on risk assessment, loss, and reward processing in PG.
3.3 FUNCTIONAL MAGNETIC RESONANCE IMAGING

Functional magnetic resonance imaging (fMRI) tasks offer insight into the neural
circuitry associated with different neuropsychological processes that may be targeted
in the treatment of gambling disorder. These tasks permit the evaluation of the neural
underpinnings of cognitive processes, such as decision-making or processing of
monetary rewards and losses (reviewed in Potenza, 2014). Data from fMRI studies
implicate similar brain regions in both substance and behavioral addictions (Leeman
and Potenza, 2013; Potenza, 2013). For example, several studies of monetary-reward
processing have identified blunted activation of the ventral striatum (VS) during
reward anticipation in gambling disorder (Balodis et al, 2012; Choi et al., 2012), res-
onating with findings in alcohol-, tobacco-, and cannabis-use disorders (reviewed in
Balodis and Potenza, 2015). Below, we will highlight findings from fMRI recent
studies not covered in recent reviews.
In a recent study examining decision-making when varying risk and ambiguity,
healthy control participants but not those with PG showed greater striatal, insular,
and prefrontal cortical activations during decision-making under risk as compared
to ambiguity, and individuals with PG as compared to those without showed greater
striatal activation during betting as compared to “safe” choices (Brevers et al., 2015).
Using a different task, Miedl and colleagues demonstrated that processing delayed
rewards during decision-making involves widespread, bilateral activation in PG sub-
jects compared to left side activation of healthy controls. In addition, indifferent
compared to sure decisions elicited greater widespread activation in PG versus con-
trol subjects, where sure decisions for PG subjects only elicited activity in the inferior
parietal and superior temporal areas, and greater activity in the cingulate gyrus,
insula, and medial frontal gyrus in healthy control subjects (Miedl et al., 2015).
Together, findings suggest a complex relationship between striatal activation and
gambling disorder. It is likely that between-study differences in task design (e.g.,
delay-discounting vs. risky choice tasks) may relate to differences in findings.
Reward type may also impact neural reactivity. Monetary and erotic rewards
have been used in order to assess possible differences between reward types. VS ac-
tivation during reward anticipation for erotic stimuli was lower compared to mone-
tary rewards in PG subjects, and this activation was correlated to subjective ratings
for erotic but not monetary rewards in PG subjects (Sescousse et al., 2013). Posterior
orbitofrontal cortical activation was greater during reward outcome for PG subjects
for monetary gains (Sescousse et al., 2013). Differences based on reward type related
to stress systems as VS activation and cortisol levels were correlated in PG subjects
in response to monetary cues (Li et al., 2014).
fMRI tasks may model aspects of electronic-gambling machines including “near-
miss” events that occur when symbols on two of three reels match. These tasks may
relate more closely to specific gambling behaviors compared to other decision-making
tasks. During near-miss events, both cocaine-dependent and PG subjects showed
greater reactivity in ventrocortical and mesolimbic areas compared to those without
either diagnosis, with PG subjects having greatest reactivity (Worhunsky et al.,
2014). During a similar task, near-miss events elicited activity in the insula and right
inferior frontal gyrus, and increased theta-band oscillations in the right orbitofrontal
cortex (OFC) and insula (Dymond et al., 2014). These data suggest task content is also
relevant to activity when comparing across addictions. Therefore, future studies should
attempt to incorporate tasks which may be more ecologically valid.
Resting-state fMRI studies may offer valuable insight into functional brain
connectivity at rest. In PG subjects, the supplementary motor area and paracingulate
cortex show reduced connectivity at rest (Tschernegg et al., 2014). The right caudate
appears more involved and the hippocampus less involved in information integration
in PG versus control subjects (Tschernegg et al., 2014). These data suggest differ-
ences in PG and non-PG groups in networks involved in self-regulation and reward
processing.
3 Neural features of gambling disorder 315
3.4 STRUCTURAL MRI

Structural MRI allows for volumetric comparison of tissue structures across different
diagnostic groups. Using this method, comparisons between PG, substance-addicted
and nonaddicted groups may improve understanding of the neural structural under-
pinnings of various addictions. Recently, smaller left hippocampal and right amyg-
dalar volumes were found in PG versus control subjects (Rahman et al., 2014).
Regional volumes were related to behavioral inhibition scores grouping PG subjects
(Rahman et al., 2014). Additionally, problem-gambling subjects displayed similar
gray matter volumes as did subjects with alcohol use disorder: lower volumes in left
superior frontal cortex, bilateral precentral cortex, right insula, left thalamus, bilat-
eral superior parietal cortex, and right supramarginal cortex (van Holst et al., 2012).
3.5 DIFFUSION TENSOR IMAGING

Diffusion tensor imaging (DTI) may assess white matter integrity. To date, two stud-
ies have used DTI to study PG. In PG versus control subjects, lower fractional an-
isotropy (FA) was present in the right and left genu of the corpus callosum, a pattern
also seen in substance abuse (Yip et al., 2011). Lower FA in the corpus callosum was
also seen in an independent study which reported widespread lower FA in PG ( Jousta
et al., 2011). Together, these studies suggest microstructural deficits present in PG
which appear not to be accounted for by neurotoxic effects of substances.
3.6 NEUROCHEMISTRY
Preclinical, ligand-based imaging, and molecular genetic research methods may all
be used to inform understanding of the role of different neurotransmitters systems in
PG (reviewed in Potenza, 2013). In this section, we will focus on recent findings
from human ligand-based and genetic studies, with an emphasis on dopamine and
serotonin (5-HT). For a discussion of findings from pharmacological treatment stud-
ies conducted in gambling disorder, see Section 5.2.
The role of dopamine in PG remains poorly understood. Dopamine has been im-
plicated in substance addictions and reward processing, among other behaviors. Pos-
itron emission tomography (PET) permits study of neurochemical and metabolic
measures. As reviewed in Potenza (2013), data from PET studies using [11C]-
raclopride suggest that individual differences in dopamine release and D2/3 receptor
availability are related to individual differences in clinical features of PG, such as
positive urgency (Clark et al., 2012) and task performance (Linnet et al., 2012) or
subjective experiences during gambling tasks ( Jousta et al., 2012).
There have been two recent PET studies using the D3-preferring radioligand
[11C]-(+)-propyl-hexahydro-naphtho-oxazin (Boileau et al., 2013, 2014). While no
significant differences in D3 receptor availability were found between individuals
with and without PG (Boileau et al., 2013, 2014), significant decreases in receptor
binding subsequent to amphetamine challenge were observed among individuals

with PG (Boileau et al., 2014).
Problem-gambling severity has been linked to the serotonin system (reviewed in
Leeman and Potenza, 2013; Potenza, 2013). A positive association between seroto-
nin 1B receptor availability and problem-gambling severity (Potenza, 2013) and a
genetic link between serotonin 2A receptors and PG have been reported; see genetic
studies, below (Wilson et al., 2013).
The relationship between dopamine and serotonin and their complementary roles
in value-adaptation and loss-chasing may be relevant to PG (Campbell-Meiklejohn
et al., 2011). Other neurotransmitter systems (e.g., opioid, cannabinoid, glutamate)
require consideration in PG.
4 GENETICS
Polymorphisms in genes encoding for dopamine-related moieties, including DRD1
Ddel, DRD2 Taq I A, and DRD4 (exon III), have been reported, although negative
results have also been reported (reviewed in Leeman and Potenza, 2013). Studies
also suggest genes coding for the serotonin transporter, 5HTTLPR, and MAO en-
zymes (e.g., MAO-A, MAO-B) may contribute to PG (reviewed in Leeman and
Potenza, 2013). An association between the C/C genotype of the 5-HT-2A receptor
gene and PG has also been reported recently (Wilson et al., 2013). Below, we review
findings from recent genetic studies, focusing on findings not covered in recent re-
views (Gyollai et al., 2014; Leeman and Potenza, 2013; Yau et al., 2014).
While candidate gene studies often fail to replicate, genome-wide association
studies (GWASs) have arguably shown more consistency, although few have been
performed in PG (one reported to date). GWAS data collected in a community-based
Australian twin sample identified six single-nucleotide polymorphisms (SNPs) as re-
lated to disordered gambling, four of which the authors interpreted as “theoretically
relevant,” although none reached genome-wide significance (Lind et al., 2012). Iden-
tified SNPs included rs8064100, located downstream of metallothionein 1X (MT1X),
previously implicated in alcohol and drug dependence (Lind et al., 2012).
Genetic contributions have been found to relate to the age of onset of gambling
but not age of onset of drinking in males; however, in females, genetic contributions
link to onsets of both behaviors (Richmond-Rakerd et al., 2014). Conversely, twin
studies suggest nondisordered gambling engagement is equally influenced by family
environmental factors in men and women (Slutske and Richmond-Rakerd, 2014).
Recently, shared environmental and genetic factors have been linked to the age of
gambling initiation predicting gambling behavior later in life (Slutske et al., 2014).
Taken together, these findings suggest a complicated relationship between genetic
contributions, environmental influences, sex, and gambling behaviors and disorders.
Twin studies offer valuable insight into relative genetic and environmental con-
tributions to PG and co-occurring disorders. The Vietnam Era Twin Registry has
demonstrated that PG shares genetic factors with both obsessive-compulsive classes
5 Treatment of gambling disorder 317
(Scherrer et al., 2015) and drug addictions (Xian et al., 2014), with environmental
contributions less important for the overlap between PG and stimulant dependence.
These findings suggest the need to identify specific genetic factors involved in these
relationships and determine the extent to which these may represent appropriate tar-
gets for behavioral or pharmacological interventions in subgroups of individuals
with PG.
5 TREATMENT OF GAMBLING DISORDER

Treatment of PG involves both pharmacological and nonpharmacological methods,
as reviewed elsewhere (Yip and Potenza, 2014). Though various treatments exist,
individuals with PG are often unlikely to seek treatment, and those that do have high
dropout rates, highlighting the need for enhanced efforts to get individuals into treat-
ment settings and maintain their attendance (Rash and Petry, 2014).
5.1 BEHAVIORAL TREATMENT

Two recent manuscripts have reviewed nonpharmacological therapies for PG
(Cowlishaw et al., 2012; Rash and Petry, 2014). Cognitive behavioral therapy
(CBT) has arguably the greatest support, with one CBT treatment adapted from that
demonstrating efficacy in the treatment of substance-use disorders and another
focused on targeting irrational cognitions. As compared to CBT for substance addic-
tions, CBT for PG may also target financial problems and financial management.
Other approaches that have shown efficacy in the treatment of PG involve imaginal
desensitization, motivational enhancement, and brief interventions like those that
show efficacy in the treatment of substance-use disorders. Mindfulness-based
approaches for PG have also been proposed and are beginning to be investigated.
Active ingredients of these therapies and biological mechanisms relating to their
efficacies have been proposed, and further research is needed to investigate how
these treatments work and for whom they might work best (Potenza et al., 2013).
5.2 PHARMACOLOGICAL TREATMENT

Serotonin selective reuptake inhibitors, dopaminergic agents, mood stabilizers, glu-
tamatergic agents, opioid-receptor antagonists, and other drugs have been investi-
gated in the treatment of PG (reviewed in Bullock and Potenza, 2012; Yip and
Potenza, 2014). Arguably, the most consistent results are from studies of opioid-
receptor antagonists (naltrexone, nalmefene), with four randomized clinical trials
(RCTs) showing varying degrees of efficacy. However, the effect size of opioid-
receptor antagonists in the treatment of PG may be modest (Bartley and Bloch,
2013), although the medication may be most helpful for specific subgroups (those
with familial histories of alcoholism or strong gambling urges). Treatment algo-
rithms have been proposed (Bullock and Potenza, 2012) largely based on
co-occurring disorders (e.g., lithium in the treatment of individuals with PG and

co-occurring bipolar-spectrum disorders) and willingness to take pharmacother-
apies. For individuals less willing to consider pharmacotherapies, n-acetyl cysteine,
a dietary supplement with glutamatergic properties, may represent an important
therapeutic possibility. Recently, in a placebo-controlled RCT of n-acetyl cysteine
in individuals with PG and nicotine dependence in which all participants received
a behavioral therapy for gambling involving CBT, motivational, and imaginal-
desensitization components, active n-acetyl cysteine was superior to placebo with
respect to reducing smoking during treatment and reducing gambling behaviors at
follow-up (Grant et al., 2014). These findings raise the intriguing possibility that
n-acetyl cysteine may lead to greater durability of gambling-related behavioral ther-
apies, perhaps augmenting a “sleeper” effect that has been described for CBT in the
treatment of substance-use disorders. However, this and other aspects of how behav-
ioral and pharmacological therapies may be used conjointly in the treatment of PG
warrant additional investigation.
6 PROBLEMATIC INTERNET USE AND IGD

The extent to which Internet use may be considered the focus of a disorder has been
debated, with some contending that the Internet may represent a vehicle for other
behaviors (e.g., gambling) that constitute the true diagnostic focus (Petry and
O’Brien, 2013). Additionally, if considered a disorder, debate exists regarding the
extent to which problematic Internet use (PIU) may represent an addiction or not.
Given these debates, we will use the term PIU in this review although other terms
(e.g., Internet addiction) have been used in the literature. PIU may be conceptualized
as involving the excessive or poorly controlled urges and behaviors relating to Inter-
net use that lead to subjective distress and/or interference in major areas of life func-
tioning. It is a heterogeneous construct that may include a multitude features relating
to sexual, social networking, and gaming behaviors. Currently, IGD is included in
Section 3 of the DSM-5 as this was determined to need more research, despite being
considered the most well studied and interfering type of Internet use at the time of
DSM-5 deliberations (Petry and O’Brien, 2013).
7 NEURAL FEATURES OF PIU

7.1 NEUROCOGNITIVE FACETS
Few neurocognitive studies have been used to assess PIU and IGD; however, differ-
ences in impulsivity have been noted. High urgency, a facet of impulsivity, has been
shown to relate to PIU (Billeux et al., 2011). Higher self-reported impulsivity was
also found in IGD and alcohol use disorder (AUD) compared to healthy controls
and GD (Choi et al., 2014). Interestingly, IGD, AUD, and healthy controls displayed
less compulsivity than did GD on a set-shifting task (Choi et al., 2014). Additional
7 Neural features of PIU 319
neurocognitive differences have been observed (see following sections). Together,

these data suggest differences between IGD and healthy populations as well as be-
tween IGD and other behavioral addictions, and these may be important consider-
ations for treatment development (Dong and Potenza, 2014).
7.2 ELECTROPHYSIOLOGY
Resting-state EEG studies are used to evaluate intrinsic neural activity which is not
elicited through a task. In a PIU population, lower absolute beta-band and greater
absolute gamma-band activities related to disorder severity and impulsivity mea-
sures (Choi et al., 2013). In those with comorbid depression, increased theta and de-
creased alpha-band power was found compared to nondepressed individuals with
PIU where nondepressed individuals presented with decreased delta- and beta-band
power compared to depressed individuals (Lee et al., 2014). These resting-state data
suggest these neurobiological differences may be markers for PIU.
Studies evaluating ERP activity, such as a Go/No-Go or Stroop task, may reflect
facets related to impulsivity and error processing. In a Go/No-Go task, N2 amplitude
was lower in PIU and P3 amplitude was larger with a longer latency, and decreased
activity in conflict detection was observed compared to healthy comparison subjects
(Dong et al., 2010). Relative to healthy comparison subjects, an incorrect response
during the No-Go condition elicited a decreased amplitude of error-related negativity
in individuals with IGD which was associated with impulsivity assessed via task per-
formance and self-report (Littel et al., 2012). Similarly, during Stroop performance,
decreased medial frontal negativity, greater reaction times, and response errors
were found during incongruent trials in the PIU group to the healthy comparison
subjects (Dong et al., 2011). Together, these studies suggest differences in impulsiv-
ity which may be evaluated through ERP tasks, and which may relate to deficits in
conflict processing and have implications for treatment development (Dong and
Potenza, 2014).
7.3 FUNCTIONAL MRI

Reward circuitry, cognitive control, cue reactivity, and craving fMRI tasks have im-
plicated some similar brain regions in PIU and substance-use disorders (reviewed in
van Rooij and Prause, 2014; Yau and Potenza, 2015; Yau et al., 2012). In particular,
mesolimbic and cortical regions relating to reward/motivation and behavioral control
may contribute to the pathophysiology of PIU. A recent meta-analysis found subjects
with IGD showed abnormal activation of the medial frontal, medial temporal, and
cingulate gyrus regions in response to a range of cognitive tasks (Meng et al., 2014).
Studies of functional connectivity may provide insight into how brain regions in-
teract in circuits. Resting-state MRI has been used to investigate task-independent
functional connectivity between regions of the mesolimbic system. Graph-
theoretical approaches have identified connectivity in limbic regions including the
amygdala, the insula, and dorsolateral prefrontal cortex (dlPFC) correlated with
features of PIU and IGD (Ko et al., 2015; Wang et al., 2015). Similarly, less func-
tional connectivity in executive-control networks was observed among individuals
with IGD compared to control subjects (Dong et al., 2015). These brain networks
have been implicated in substance addictions and may contribute to the development
and maintenance of addictive behaviors. Altered connectivity between regions of the
default-mode network has also been observed among individuals with PIU, and de-
gree of connectivity was related to PIU severity (Wee et al., 2014).
7.4 STRUCTURAL MRI

Several studies have also investigated structural abnormalities that may relate to PIU.
Reduced regional gray matter volume has been observed in key nodes of executive-
control networks (e.g., frontoinsular cortex, anterior cingulate cortex, dlPFC, and
posterior parietal cortex) in association with greater PIU severity (Li et al., 2015).
Furthermore, these differences correlated with performance on the Stroop task
and may, therefore, reflect reduced inhibitory control and cognitive efficiency. De-
creased cortical thickness (Hong et al., 2013) has also been observed in regions of the
executive-control network among individuals with PIU.
In light of the recent DSM categorization changes relating to conditions with ad-
dictive potential, comparing PIU and substance-abusing populations may provide in-
sight into the most appropriate categorization of PIU. Commonalities and differences
exist between the two groups and a better understanding of this can help improve
diagnosis (Yau et al., 2012). For example, among both IGD and alcohol-dependent
populations, negative functional connectivity between the dlPFC and the OFC and
positive connectivity between the dlPFC and the ACC have been observed (Han
et al., 2015). However, subjects with IGD showed negative connectivity between
the dlPFC and regions of the temporal lobe, and the striatum, whereas alcohol-
dependent subjects had positive connectivity. Kim and colleagues (2015) recently
found increased regional homogeneity in the posterior cingulate cortex in both
IGD and alcohol-dependent individuals; however, regional homogeneity appeared
selectively reduced in the superior temporal gyrus in IGD.
7.5 DIFFUSION TENSOR IMAGING

DTI studies have suggested poorer white matter integrity in PIU, although not con-
sistently (Yau et al., 2012). In one study of adolescents, lower FA was observed in the
OFC, corpus callosum, cingulum, inferior fronto-occipital fasciculus, corona radiata,
and internal and external capsules, with FA measures in the genu of the corpus
collusum inversely correlating with measures of anxiety and those in the external
capsule relating inversely correlating with PIU severity (Lin et al., 2012).
A separate study found lower white matter density in the inferior frontal gyrus,
insula, amygdala, and anterior cingulate in IGD subjects relatively to control subjects
(Lin et al., 2015).
9 Treatment 321
7.6 NEUROCHEMISTRY
Several neurotransmitter systems may contribute to PIU. Of these, the dopaminergic
system has arguably received the most research attention. Years of problematic gam-
ing was negatively correlated with D2-like receptor availability in the striatum and
IGD subjects showed decreased glucose metabolism in the OFC, insula, and limbic
regions (Tian et al, 2014). In a separate study, dopamine transporter expression in the
striatum was significantly lower in individuals with PIU compared to healthy control
subjects (Hou et al., 2012).
Beyond the dopaminergic system, other neurochemical systems have shown dif-
ferences which may underlie PIU. Recently, lower levels of N-acetyl aspartate
(NAA) and cystolic, choline-containing compound (Cho) levels were observed in
the medial temporal cortices of IGD patients. Additionally, lower levels of NAA
and Cho in the right frontal cortex were also seen, and the NAA was inversely related
to Young Internet Addiction Scale scores and perseverative responses during the
Wisconsin Card Sorting Task (Han et al., 2014). Further study of the underlying neu-
rochemical differences among individuals with PIU is needed in order to guide treat-
ment development efforts.
8 GENETICS
Genetic mechanisms underlying PIU are poorly understood and currently only pre-
liminary studies exists. As with disordered gambling, relationships between PIU and
the Taq1A1 allele of the DRD2 gene (Han et al., 2007) and homozygosity of the short
allelic variant of the 5-HTTLPR gene (Lee et al., 2008) have been associated with
PIU. However, these studies warrant replication and verification in larger samples,
and other approaches (twin and GWAS studies) warrant undertaking.
9 TREATMENT
Few interventions have been systematically tested for PIU or IGD. Treatment strat-
egies may be particularly important for adolescents and young adults given high
prevalence estimates among these age groups (Spada, 2014).
9.1 BEHAVIORAL TREATMENT

Behavioral treatments have yet to be systematically studied in the context of PIU.
Preliminary studies of CBT adapted for PIU (and more specifically in certain studies
of IGD and problematic Internet pornography viewing) has demonstrated prelimi-
nary positive benefits (Twohig and Crosby, 2010; W€olfling et al., 2014; Young,
2013). Such CBT approaches aim to help individuals examine emotional motives
and identify problematic cognition that may prompt them to engage excessively
in online activities. As with disordered gambling, individuals are encouraged to
explore alternative ways to satisfy those needs (e.g., developing other recreational
pursuits) and to correct maladaptive thinking patterns. Family therapies involving
increased socialization efforts have also been examined in PIU (Liu et al., 2015),
with preliminary reports of possible treatment-related changes in striatal responsivity
(Han et al., 2012). Other behavioral interventions (e.g., solution-focused brief ther-
apy, mindfulness-based interventions) may also be helpful given the proposed addic-
tion model of PIU but their efficacy has yet to be studied directly.
9.2 PHARMACOLOGICAL TREATMENT

Psychostimulants, opioid-receptor antagonists (e.g., naltrexone), antiepileptics, an-
tipsychotics (e.g., olanzapine), antidepressants (e.g., bupropion), and glutamate-
receptor antagonists have explored in treatments for PIU (reviewed in Camardese
et al., 2012; Przepiorka et al., 2014; Winkler et al., 2013). Successful treatment
may link changes in specific domains (e.g., depression, cognitive flexibility), and
as in PG, comorbidity may be important to consider (Przepiorka et al., 2014). Al-
though many pharmacotherapies have been explored in the treatment of PIU,
placebo-controlled RCTs of significant size and duration are largely lacking, and
as is the case with PG, no medications have approval by the U.S. Food and Drug
Administration (FDA) with an indication for treating PIU or IGD.
10 FUTURE DIRECTIONS
While much research has been conducted recently on PG, PIU, and IGD, many re-
search gaps exist, with arguably greater gaps and controversies for Internet-related
behaviors and disorders. For example, research criteria for IGD have only recently
been proposed, and these do not cover other forms of Internet use (e.g., social net-
working, pornography viewing) that might be problematic for individuals (Rehbein
and M€ oßle, 2013). Additionally, the absence of agreed-upon criteria for PIU has led
to marked variations in reported prevalence estimates and assessment of public
health impacts (Petry and O’Brien, 2013). While treatment development efforts
for PG have led to the availability of efficacious behavioral therapies for PG, such
studies are at earlier stages for PIU. For PG, PIU, and IGD, no pharmacotherapy trials
have led to the availability of medications with FDA indications for the disorders.
With respect to prevention efforts, healthy levels of engagement in gambling, gam-
ing, and Internet use remain discussed and/or debated. In these efforts, potentially
vulnerable individuals should be considered, especially youth. Other factors should
also be considered; for example, most studies of PG, PIU, and IGD have focused on
males, and sex differences warrant consideration, particularly for specific Internet-
related behaviors like social networking. Additionally, health disparities related to
race/ethnicity should also be considered. In this context, neurobiological findings
should be used to inform advancement of policy, prevention, and treatment efforts
relating to behavioral addictions.
References 323
ACKNOWLEDGMENTS
This was supported by P20 DA027844, T32 AA015496, T32 DA007238, CASA Columbia,
and the National Center for Responsible Gaming. The content of the manuscript reflects
the views of the authors and not necessarily the funding agencies. The funding agencies
did not have input into the content of the manuscript.
Disclosures: The authors report that they have no financial conflicts of interest with respect
to the content of this manuscript. Dr. Potenza has received financial support or compensation
for the following: Dr. Potenza has consulted for and advised Somaxon, Boehringer Ingelheim,
Lundbeck, Ironwood, Shire, INSYS, and RiverMend Health; has received research support
from the National Institutes of Health, Veteran’s Administration, Mohegan Sun Casino,
the National Center for Responsible Gaming, and Forest Laboratories, Ortho-McNeil,
Oy-Control/Biotie, Glaxo-SmithKline, Pfizer, and Psyadon pharmaceuticals; has participated
in surveys, mailings, or telephone consultations related to drug addiction, impulse control dis-
orders, or other health topics; has consulted for gambling entities, law offices, and the federal
public defender’s office in issues related to impulse control disorders; provides clinical care in
the Connecticut Department of Mental Health and Addiction Services Problem Gambling Ser-
vices Program; has performed grant reviews for the National Institutes of Health and other
agencies; has edited or guest-edited journal sections; has given academic lectures in grand
rounds, CME events, and other clinical or scientific venues; and has generated books or book
chapters for publishers of mental health texts.
REFERENCES
ders (DSM-IV-R). American Psychiatric Press, Inc., Washington, DC.
ders (DSM-5). American Psychiatric Press, Inc., Washington, DC.
Balodis, I.M., Potenza, M.N., 2015. Anticipatory reward processing in addicted populations: a
focus on the monetary incentive delay task. Biol. Psychiatry 77 (5), 434–444.
Balodis, I.M., Kober, H., Worhunsky, P.D., Stevens, M.C., Pearlson, G.D., Potenza, M.N.,
2012. Diminished frontostriatal activity during processing of monetary rewards and losses
in pathological gambling. Biol. Psychiatry 71 (8), 749–757.
Bartley, C.A., Bloch, M.H., 2013. Meta-analysis: pharmacological treatment of pathological
gambling. Expert. Rev. Neurother. 13 (8), 887–894.
Billeux, J., Chanal, J., Khazaal, Y., Rochat, L., Gay, P., Zullino, D., Van der Linden, M., 2011.
Psychological predictors of problematic involvement in massively multiplayer online role-
playing games: illustration in a sample of male cybercafé players. Psychopathology
44, 165–171.
Boileau, I., Payer, D., Chugani, B., Lobo, D., Behzadi, A., Rusjan, P., Houle, S., Wilson, A.,
Warsh, J., Kish, S., Zack, M., 2013. The D2/3 dopamine receptor in pathological gam-
bling: a positron emission tomography study with [11C]-(+)-propyl-hexahydro-naphtho-
oxazin and [11C]raclopride. Addiction 108 (5), 953–963.
Boileau, I., Payer, D., Chugani, B., Lobo, D.S., Houle, S., Wilson, A.A., Warsh, J., Kish, S.,
Zack, M., 2014. In vivo evidence for greater amphetamine-induced dopamine release in
pathological gambling: a positron emission tomography study with [(11)C-(+)-PHNO.
Mol. Psychiatry 19 (12), 1305–1313.
Brevers, D., Cleeremans, A., Goudriaan, A.E., Bechara, A., Kornreich, C., Verbanck, P.,
Noël, X., 2013. Decision making under ambiguity but not under risk is related to problem
gambling severity. Psychiatry Res. 200, 568–574.
Brevers, D., Bechara, A., Hermoye, L., Divano, L., Kornreich, C., Verbanck, P., Noel, X.,
2015. Comfort for uncertainty in pathological gamblers: a fMRI study. Behav. Brain
Res. 278C, 262–270.
Bullock, S., Potenza, M.N., 2012. Neuropsychology and treatment. Psychopharmacology
1, 67–85.
Camardese, G., De Risio, L., Di Nicola, M., Pizi, G., Janiri, L., 2012. A role for pharmaco-
therapy in the treatment of “Internet addiction”. Clin. Neuropharmacol. 35 (6), 283–289.
Campbell-Meiklejohn, D., Wakeley, J., Herbert, V., Cook, J., Scollo, P., Ray, M.K., Selvaraj, S.,
Passingham, R.E., Cowen, P., Rogers, R.D., 2011. Serotonin and dopamine play complimen-
tary roles in gambling to recover losses. Neuropsychopharmacology 36, 402–410.
Choi, J.S., Shin, Y.C., Jung, W.H., Jang, J.H., Kang, D.H., Choi, C.H., Choi, S.W., Lee, J.Y.,
Hwang, J.Y., Kwon, J.S., 2012. Altered brain activity during reward anticipation in
pathological gambling and obsessive-compulsive disorder. PLoS ONE 7 (9), e45938.
Choi, J.S., Park, S.M., Lee, J., Hwang, J.Y., Jung, H.Y., Choi, S.W., Kim, D.J., Oh, S., Lee, J.Y.,
2013. Resting-state beta and gamma activity in Internet addiction. Int. J. Psychophysiol.
89, 328–333.
Choi, S.W., Kim, H.S., Kim, G.Y., Jeon, Y., Park, S.M., Lee, J.Y., Jung, H.Y., Sohn, B.K.,
Choi, J.S., Kim, D.J., 2014. Similarities and differences among Internet gaming disorder,
gambling disorder and alcohol use disorder: a focus on impulsivity and compulsivity.
J. Behav. Addict. 3 (4), 246–253.
Clark, L., Stokes, P.R., Wu, K., Michalczuk, R., Benecke, A., Watson, B.J., Egerton, A.,
Piccini, P., Nutt, D.J., Bowden-Jones, H., Lingford-Hughes, A.R., 2012. Striatal dopamine
D2/D3 receptor binding in pathological gambling is correlated with mood-related impul-
sivity. NeuroImage 63, 40–46.
Cowlishaw, S., Merkouris, S., Dowling, N., Anderson, C., Jackson, A., Thomas, S., 2012.
Psychological therapies for pathological and problem gambling. Cochrane Database Syst.
Rev. 11. 1–91. http://dx.doi.org/10.1002/14651858.CD008937.pub2.
Dong, G., Potenza, M.N., 2014. A cognitive-behavioral model of Internet gaming disorder:
theoretical underpinnings and clinical implications. J. Psychiatr. Res. 58, 7–11.
Dong, G., Lu, Q., Zhou, H., Zhao, X., 2010. Impulse inhibition in people with Internet addic-
tion disorder: electrophysiological evidence from a Go/NoGo study. Neurosci. Lett.
485, 138–142.
Dong, G., Zhou, H., Zhao, X., 2011. Male Internet addicts show impaired executive control
ability: evidence from a color-word Stroop task. Neurosci. Lett. 499, 114–118.
Dong, G., Lin, X., Potenza, M.N., 2015. Decreased functional connectivity in an executive
control network is related to impaired executive function in Internet gaming disorder.
Prog. Neuropsychopharmacol. Biol. Psychiatry 57, 76–85.
Dymond, S., Lawrence, N.S., Dunkley, B.T., Yuen, K.S.L., Hinton, E.C., Dixon, M.R.,
Cox, W.M., Hoon, A.E., Munnelly, A., Muthukumaraswamy, S.D., Singh, K.D., 2014.
Almost winning: induced MEG theta power in insula and orbitofrontal cortex increases
during gambling near-misses and is associated with BOLD signal and gambling severity.
NeuroImage 91, 210–219.
Grant, J.E., Odlaug, B.L., Chamberlain, S.R., Potenza, M.N., Schreiber, L.R.N., Donahue, C.B.,
Kim, S.W., 2014. A randomized, placebo-controlled trial of N-acetyl cysteine plus
References 325
imaginal desensitization for nicotine-dependent pathological gamblers. J. Clin. Psychiatry

75, 39–45.
Gyollai, Á., Griffiths, M.D., Barta, C., Vereczkei, A., Urbán, R., Kun, B., K€ ok€onyei, G.,
Székely, A., Sasvári-Székely, M., Blum, K., Demetrovics, Z., 2014. The genetics of prob-
lem and pathological gambling: a systematic review. Curr. Pharm. Des. 20, 3993–3999.
Han, D.H., Lee, Y.S., Yang, K.C., Kim, E.Y., Lyoo, I.K., Renshaw, P.F., 2007. Dopamine
genes and reward dependence in adolescents with excessive internet video game play.
J. Addict. Med. 1 (3), 133–138.
Han, D.H., Kim, S.M., Lee, Y.S., Renshaw, P.F., 2012. The effect of family therapy on the
changes in the severity of on-line game play and brain activity in adolescents with
on-line game addiction. Psychiatry Res. 20 (22), 126–131.
Han, D.H., Lee, Y.S., Shi, X., Renshaw, P.F., 2014. Proton magnetic resonance spectroscopy
(MRS) in on-line game addiction. J. Psychiatr. Res. 58, 63–68.
Han, J.W., Han, D.H., Bolo, N., Kim, B.N., Renshaw, P.F., 2015. Differences in functional
connectivity between alcohol dependence and internet gaming disorder. Addict. Behav.
41, 12–19.
Hewig, J., Kretschmer, N., Trippe, R.H., Hecht, H., Coles, M.G.H., Holroyd, C.B.,
Miltner, W.H.R., 2010. Hypersensitivity to reward in problem gamblers. Biol. Psychiatry
67, 781–783.
Hong, S.B., Kim, J.W., Choi, E.J., Kim, H.H., Suh, J.E., Kim, C.D., Klauser, P., Whittle, S.,
Yucel, M., Pantelis, C., Yi, S.H., 2013. Reduced orbitofrontal cortical thickness in male
adolescents with internet addiction. Behav. Brain Funct. 9 (11), 9081–9089.
Hou, H., Jia, S., Hu, S., Fan, R., Sun, W., Sun, T., Zhang, H., 2012. Reduced striatal dopamine
transporters in people with internet addiction disorder. J. Biomed. Biotechnol.
2012, 854524.
Jousta, J., Saunavaara, J., Parkkola, R., Niemelä, S., Kaasinen, V., 2011. Extensive
abnormality of brain white matter integrity in pathological gambling. Psychiatry Res.
194, 340–346.
Jousta, J., Johansson, J., Niemelä, S., Ollikainen, A., Hirvonen, M.K., Piepponen, P.,
Arponen, E., Alho, H., Voon, V., Rinne, J.O., Hietala, J., Kaasinen, V., 2012. Mesolimbic
dopamine release is linked to symptom severity in pathological gambling. NeuroImage
60, 1992–1999.
Kim, H., Kim, Y.K., Gwak, A.R., Lim, J.A., Lee, J.Y., Jung, H.Y., Sohn, B.K., Choi, S.W.,
Kim, D.J., Choi, J.S., 2015. Resting-state regional homogeneity as a biological marker for
patients with Internet gaming disorder: a comparison with patients with alcohol use dis-
order and healthy controls. Prog. Neuropsychopharmacol. Biol. Psychiatry 14 (60),
104–111.
Ko, C.H., Hsieh, T.J., Wang, P.W., Lin, W.C., Yen, C.F., Chen, C.S., Yen, J.Y., 2015.
Altered gray matter density and disrupted functional connectivity of the amygdala in
adults with Internet gaming disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry
57, 185–192.
Kreussel, L., Hewig, J., Kretschmer, N., Hecht, H., Coles, M.G.H., Miltner, W.H.R., 2013.
How bad was it? Differences in the time course of sensitivity to the magnitude of loss
in problem gamblers and controls. Behav. Brain Res. 247, 140–145.
Lee, Y.S., Han, D., Yang, K.C., Daniels, M.A., Na, C., Kee, B.S., Renshaw, P.F., 2008.
Depression like characteristics of 5HTTLPR polymorphism and temperament in excessive
internet users. J. Affect. Disord. 1–2, 165–169.
Lee, J., Hwang, J.Y., Park, S.M., Jung, H.Y., Choi, S.W., Kim, D.J., Lee, J.Y., Choi, J.S., 2014.
Differential resting-state EEG patterns associated with comorbid depression in Internet
addiction. Prog. Neuropsychopharmacol. Biol. Psychiatry 50, 21–26.
Leeman, R.F., Potenza, M.N., 2012. Similarities and differences between pathological
gambling and substance use disorders: a focus on impulsivity and compulsivity.
Leeman, R.F., Potenza, M.N., 2013. A targeted review of the neurobiology and genetics of
behavioral addictions: an emerging area of research. Can. J. Psychiatry 58 (5), 260–273.
Li, Y., Sescousse, G., Dreher, J.C., 2014. Endogenous cortisol levels are associated with
an imbalanced striatal sensitivity to monetary versus non-monetary cues in pathological
gamblers. Front. Behav. Neurosci. 8, 83.
Li, W., Li, Y., Yang, W., Zhang, Q., Wei, D., Li, W., Hitchman, G., Qiu, J., 2015. Brain struc-
ture and functional connectivity associated with individual difference in Internet tendency
in healthy young adults. Neuropsychologia 70, 134–144.
Lin, F., Zhou, Y., Du, Y., Qin, L., Zhao, Z., Xu, J., Lei, H., 2012. Abnormal white matter in-
tegrity in adolescents with internet addiction disorder: a tract-based spatial statistics study.
PLoS One 7 (1), e30253.
Lin, X., Dong, G., Wang, Q., Du, X., 2015. Abnormal gray matter and white matter volume in
‘Internet gaming addicts’. Addict. Behav. 40, 137–143.
Lind, P.A., Zhu, G., Montgomery, G.W., Madden, P.A., Heath, A.C., Martin, N.G.,
Slutske, W.S., 2012. Genome-wide association study of a quantitative disordered gam-
bling trait. Addict. Biol. 18 (3), 511–522.
Linnet, J., Mouridsen, K., Peterson, E., Møller, A., Doudet, D.J., Gjedde, A., 2012. Striatal
dopamine release codes uncertainty in pathological gambling. Psychiatry Res. 204, 55–60.
Littel, M., van den Berg, I., Luijten, M., van Rooij, A.J., Keemink, L., Franken, I.H.A., 2012.
Error processing and response inhibition in excessive computer game players: an event-
related potential study. Addict. Biol. 17, 934–947.
Liu, Q.X., Fang, X.Y., Yan, N., Zhou, Z.K., Yuan, X.J., Lan, J., Liu, C.Y., 2015. Multi-family
group therapy for adolescent Internet addiction: exploring the underlying mechanisms.
Addict. Behav. 42, 1–8.
Lole, L., Gonsalvez, C.J., Barry, R.J., 2015. Reward and punishment hyposensitivity in prob-
lem gamblers: a study of event-related potentials using a principal components analysis.
Clin. Neurophysiol. 126 (7), 1295–1309.
Meng, Y.J., Deng, W., Wang, H.Y., Guo, W.J., Li, T., Lam, C., Lin, X., 2014. Reward pathway
dysfunction in gambling disorder: a meta-analysis of functional magnetic resonance
imaging studies. Behav. Brain Res. 275, 243–251.
Miedl, S.F., Fehr, T., Herrmann, M., Meyer, G., 2014. Risk assessment and reward processing
in problem gambling investigated by event-related potentials a fMRI-constrained source
analysis. BMC Psychiatry 14, 229–240.
Miedl, S.F., Wiswede, D., Marco-Pollares, J., Ye, Z., Fehr, T., Herrmann, M., Munte, T.F.,
2015. The neural basis of impulsive discounting in pathological gamblers. Brain Imaging
Behav. epub ahead of print. http://link.springer.com/article/10.1007%2Fs11682-015-
9352-1 (accessed 28.09.15.).
Noël, X., Brevers, D., Bechara, A., 2013. A neurocognitive approach to understanding the neu-
robiology of addiction. Curr. Opin. Neurobiol. 23 (4), 632–638.
Oberg, S.A.K., Christie, G.J., Tata, M.S., 2011. Problem gamblers exhibit reward hypersen-
sitivity in medial frontal cortex during gambling. Neuropsychologia 49, 3768–3775.
References 327
Petry, N.M., O’Brien, C.P., 2013. Internet gaming disorder and the DSM-5. Addiction 108 (7),
1186–1187.
Potenza, M.N., 2006. Should addictive disorders include non-substance-related conditions?
Addiction 101, 142–151.
Potenza, M.N., 2013. Neurobiology of gambling behaviors. Curr. Opin. Neurobiol. 23 (4),
660–667.
Potenza, M.N., 2014. Non-substance addictive behaviors in the context of DSM-5. Addict.
Behav. 39 (1), 1–2.
Potenza, M.N., Balodis, I.M., Franco, C.A., Bullock, S., Xu, J., Grant, J.E., 2013. Neurobio-
logical considerations in understanding behavioral treatments for pathological gambling.
Psychol. Addict. Behav. 27, 380–392.
Przepiorka, A.M., Blachnio, A., Miziak, B., Czuczwar, S.J., 2014. Clinical approaches to treat-
ment of Internet addiction. Pharmacol. Rep. 66 (2), 187–191.
Rahman, A.S., Xu, J., Potenza, M.N., 2014. Hippocampal and amygdalar volumetric differ-
ences in pathological gambling: a preliminary study of the associations with the behavioral
inhibition system. Neuropsychopharmacology 39, 738–745.
Rash, C.J., Petry, N.M., 2014. Psychological treatments for gambling disorder. Psychol. Res.
Behav. Manag. 7, 285–295.
Rehbein, F., M€oßle, T., 2013. Video game and Internet addiction: is there a need for differ-
entiation? SUCHT 59 (3), 129–142.
Richmond-Rakerd, L.S., Slutske, W.S., Heath, A.C., Martin, N.G., 2014. Genetic and environ-
mental influences on the ages of drinking and gambling initiation: evidence for distinct
aetiologies and sex differences. Addiction 109 (2), 323–331.
Scherrer, J.F., Xian, H., Slutske, W.S., Eisen, S.A., Potenza, M.N., 2015. Associations be-
tween obsessive-compulsive classes and pathological gambling in a national cohort of
male twins. JAMA Psychiatry 72 (4), 342–349.
Sescousse, G., Barbalat, G., Domenech, P., Dreher, J.C., 2013. Imbalance in the sensitivity to
different types of rewards in pathological gambling. Brain 136 (6), 2527–2538.
Slutske, W.S., Richmond-Rakerd, L.S., 2014. A closer look at the evidence for sex differences
in the genetic and environmental influences on gambling in the National Longitudinal
Study of Adolescent health: from disordered to ordered gambling. Addiction 109 (1),
120–127.
Slutske, W.S., Deutsch, A.R., Richmond-Rakerd, L.S., Chernyavskiy, P., Statham, D.J.,
Martin, N.G., 2014. Test of a potential causal influence of earlier age of gambling initiation
on gambling involvement and disorder: a multilevel discordant twin design. Psychol.
Addict. Behav. 28 (4), 1177–1189.
Spada, M.M., 2014. An overview of problematic Internet use. Addict. Behav. 39, 3–6.
Tian, M., Chen, Q., Zhang, Y., Du, F., Hou, H., Chao, F., Zhang, H., 2014. PET imaging re-
veals brain functional changes in internet gaming disorder. Nucl. Med. Mol. Imaging
41 (7), 1388–1397.
Tschernegg, M., Crone, J.S., Eigenberger, T., Schwartenbeck, P., Fauth-Bühler, M.,
Lemènager, T., Mann, K., Thon, N., Wurst, F.M., Kronbichler, M., 2014. Abnormalities
of functional brain networks in pathological gambling: a graph-theoretical approach.
Front. Hum. Neurosci. 7, 625. http://journal.frontiersin.org/article/10.3389/fnhum.2013.
00625/abstract; (accessed 28.09.15.).
Twohig, M.P., Crosby, J.M., 2010. Acceptance and commitment therapy as a treatment for
problematic Internet pornography viewing. Behav. Ther. 41, 285–295.
Van Holst, R.J., vna den Brink, W., Veltman, D.J., Goudriaan, A.E., 2010. Why gamblers fail
to win: a review of cognitive and neuroimaging findings in pathological gambling. Neu-
rosci. Biobehav. Rev. 34, 87–107.
Van Holst, R.J., de Ruiter, M.B., van den Brink, W., Veltman, D.J., Goudriaan, A.E., 2012.
A voxel-based morphometry study comparing problem gamblers, alcohol abusers, and
healthy controls. Drug Alcohol Depend. 124, 142–148.
Van Rooij, A.J., Prause, N., 2014. A critical review of “Internet addiction” criteria with sug-
gestions for the future. J. Behav. Addict. 3 (4), 203–213.
Wang, C.W., Ho, R.T., Chan, C.L., Tse, S., 2015. Exploring personality characteristics of
Chinese adolescents with internet-related addictive behaviors: trait differences for gaming
addiction and social networking addiction. Addict. Behav. 42, 32–35.
Wee, C.Y., Zhao, Z., Yap, P.T., Wu, G., Shi, F., Price, T., Du, Y., Xu, J., Zhou, Y., Shen, D.,
2014. Disrupted brain functional network in internet addiction disorder: a resting-state
functional magnetic resonance imaging study. PLoS One 9 (9), e107306.
Wilson, D., da Silva Lobo, D.S., Tavares, H., Gentil, V., Vallada, H., 2013. Family-based as-
sociation analysis of serotonin genes in pathological gambling disorder: evidence of vul-
nerability risk in the 5HT-2A receptor gene. J. Mol. Neurosci. 49, 550–553.
Winkler, A., D€orsing, B., Rief, W., Shen, Y., Glombiewski, J.A., 2013. Treatment of internet
addiction: a meta analysis. Clin. Psychol. Rev. 33, 317–329.
W€olfling, K., Beutel, M.E., Dreier, M., Muller, K.W., 2014. Treatment outcomes in patients
with internet addiction: a clinical pilot study on the effects of a cognitive-behavioral ther-
apy program. Biomed. Res. Int. 2014, 425924. http://www.hindawi.com/journals/bmri/
2014/425924/(accessed 28.09.15.).
Worhunsky, P.D., Malison, R.T., Rogers, R.D., Potenza, M.N., 2014. Altered neural correlates
of reward and loss processing during simulated slot-machine fMRI in a pathological gam-
bling and cocaine dependence. Drug Alcohol Depend. 145, 77–86.
Xian, H., Giddens, J.L., Scherrer, J.F., Eisen, S.A., Potenza, M.N., 2014. Environmental fac-
tors selectively impact co-occurrence of problem/pathological gambling with specific
drug-use disorders in male twins. Addiction 109 (4), 635–644.
Yan, W.S., Li, Y.H., Xiao, L., Zhu, N., Bechara, A., Sui, N., 2014. Working memory and
affective decision-making in addiction: a neurocognitive comparison between heroin
addicts, pathological gamblers and healthy controls. Drug Alcohol Depend. 134, 194–200.
Yau, Y.H.C., Crowley, M.J., Mayes, L.C., Potenza, M.N., 2012. Are internet use and video-
game playing addictive behaviors? Biological, clinical and public health implications for
youths and adults. Minerva Psichiatr. 53, 153–170.
Yau, Y.H.C., Yip, S.W., Potenza, M.N., 2014. Principles of Addiction Medicine, fifth ed.
Lippincott Williams & Wilkins, Philadelphia, PA.
Yau, Y.H.C., Potenza, M.N., 2015. Gambling disorder and other behavioral addictions: rec-
ognition and treatment. Harv. Rev. Psychiatr. 23 (2), 134–146.
Yip, S.W., Potenza, M., 2014. Treatment of gambling disorders. Curr. Treat. Options Neurol.
1 (2), 189–203.
Yip, S.W., Lacadie, C., Xu, J., Worhunsky, P.D., Fulbright, R.K., Constable, R.T.,
Potenza, M.N., 2011. Reduced genual corpus callosal white matter integrity in patholog-
ical gambling and its relationship to alcohol abuse or dependence. World J. Biol. Psychi-
atry 14, 129–138.
Young, K.S., 2013. Treatment outcomes using CBT-IA with Internet-addicted patients.
J. Behav. Addict. 2 (4), 209–215.
CHAPTER
Neural systems implicated

in obesity as an addictive
disorder: from biological
to behavioral mechanisms
17
Erica M. Schulte*, Sonja Yokum†, Marc N. Potenza{,},}, Ashley N. Gearhardt*,1
*Department of Psychology, University of Michigan, Ann Arbor, MI, USA
†
Oregon Research Institute, Eugene, OR, USA
{
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
}
Department of Neurobiology, Child Study Center, Yale University School of Medicine,
New Haven, CT, USA
}
CASAColumbia, Yale University School of Medicine, New Haven, CT, USA
1
Corresponding author: Tel.: (734)647-3920; Fax: (734)763-7744,
Abstract
Contributing factors to obesity have been identified, yet prevention and treatment efforts have
had limited long-term success. It has recently been suggested that some individuals may ex-
perience an addictive-like response to certain foods, such as losing control over consumption
and continued consumption despite negative consequences. In support, shared biological and
behavioral features seem to exist between “food addiction” and traditional substance-use dis-
orders. “Food addiction” may be another important contributor to obesity. The current chapter
reviews existing literature regarding neural systems implicated similarly in obesity and addic-
tion, discusses unique considerations for addictive-like eating, and proposes directions for fu-
ture research regarding “food addiction” as an emerging construct for addiction medicine.
Keywords
Obesity, Addiction, Substance dependence, Food addiction, Reward
1 INTRODUCTION
As obesity rates continue to rise, increased attention has been given to mechanisms
associated with overeating behaviors. It has been proposed that an addictive-like
329
330 CHAPTER 17 Common neural systems in obesity and addiction
Addictive-like Traditional
eating in obesity addictive disorders
Certain foods or food attributes Presence of physical

may be capable of triggering
Shared neural and/or psychological
addictive responses systems in obesity and withdrawal symptoms
addiction
Addiction only develops in Varying degrees of
vulnerable individuals intoxication
Reward dysfunction
Likely no severe physical Addiction only
withdrawal or intoxication Impulsivity develops in vulnerable
individuals
Early developmental exposure Emotion
to certain foods and absence of dysregulation
societal restrictions may pose
unique threat
FIGURE 1
Shared neural systems in obesity and addiction and unique features for addictive-like eating
and traditional addictive disorders.
process may underlie problematic eating for some individuals (Gearhardt et al.,
2009b), although this point has been debated (Ziauddeen et al., 2012). Significant
behavioral overlap exists between obesity and addictive disorders (particularly for
some groups like those with Binge Eating Disorder; Gearhardt et al., 2011b), such
as a loss of control over consumption and continued consumption despite negative
consequences (Gearhardt et al., 2009a). The following chapter will review literature
regarding shared neural systems in traditional addictive disorders and obesity (see
Fig. 1), discuss differentiating factors of addictive-like eating, and offer essential
next steps in neuroimaging research for “food addiction.”
2 SHARED NEURAL SYSTEMS: REWARD DYSFUNCTION

Dopamine (DA) is a main catecholamine neurotransmitter implicated in reinforce-
ment- and reward-related processes, such as motivation and craving. Food and drugs
of abuse both increase DA signaling in the mesolimbic dopaminergic system (Heinz
et al., 2004; Wang et al., 2002). Consumption of high-sugar or high-fat food results in
DA release in the striatum in animals (Avena et al., 2009) and humans, with the
amount released correlating with meal pleasantness ratings (Small et al., 2003)
and energy density (Ferreira et al., 2012). In humans, consumption of palatable food
is associated with increased activation in the reward-related circuitry, including the
dorsal- and ventral striatum and orbitofrontal cortex (OFC; Stice et al., 2013a).
2 Shared neural systems: reward dysfunction 331
Likewise, all addictive drugs lead to DA release in the striatum and associated meso-
limbic regions (Kalivas and O’Brien, 2008).
Utilizing functional magnetic resonance imaging (fMRI), previous research has
observed parallels in neural responsivity to food/drug cues and intake between obe-
sity and substance-use disorders (Tang et al., 2012). Obese versus lean humans show
greater responsivity of brain regions associated with reward (e.g., striatum, amyg-
dala, OFC) and attention (e.g., anterior cingulate cortex, ACC) to pictures of
high-fat/sugar foods (versus control stimuli; Martin et al., 2010; Stice et al.,
2010b) and to pictorial cues that signal impending palatable food receipt (Ng
et al., 2011; Stice et al., 2008). Similarly, humans with, versus without,
substance-use disorders show greater activation of reward regions (e.g., VTA, amyg-
dala) and attention regions (e.g., ACC) to drug-related cues (Due et al., 2002; Myrick
et al., 2004).
One distinct feature of addictive disorders is the transition from initially
consuming drugs of abuse for their reinforcing properties to compulsive, habitual
self-administration (Everitt and Robbins, 2005). Consuming drugs of abuse or highly
palatable foods for hedonic effects (liking) activates the ventral striatum, whereas
habitual, compulsive self-administration (wanting) appears to differentially impli-
cate dorsal striatal regions (Everitt and Robbins, 2005; Volkow et al., 2006).
One proposed mechanism underlying the transition from “liking” to “wanting” is
incentive sensitization (Robinson and Berridge, 1993). This explanation suggests
that chronic consumption of addictive substances or highly palatable foods may re-
sult in sensitization of the DA system and increased salience of drug- and food-
specific cues for some individuals (Berridge, 2009). In support, animal experiments
indicate that firing of striatal and ventral pallidal DA neurons initially occurs in re-
sponse to receipt of a novel palatable food, but that after repeated pairings of palat-
able food intake and cues that signal impending receipt of that food, DA neurons
begin to fire in response to reward-predictive cues and no longer fire in response
to food receipt (Tobler et al., 2005). In humans, midbrain and medial OFC activity
in response to milkshake receipt positively correlated with subsequent ad libitum
milkshake consumption, and BOLD response in the ventral striatum during exposure
to food images positively correlated with later snack consumption (Lawrence et al.,
2012; Nolan-Poupart et al., 2013). Healthy weight adolescents who were eating be-
yond basal metabolic needs (per objective measures) versus those who were not
showed greater BOLD response during cues predicting impending palatable food re-
ceipt in regions that encode reward (striatum), salience (precuneus), and visual pro-
cessing and attention (visual and anterior cingulate cortices; Burger and Stice, 2013).
These latter data suggest that overeating, even if it has not yet resulted in excess
weight gain, may be accompanied by elevated responsivity to food-predictive cues
in reward and attentional regions. For persons susceptible to these neuroplastic
changes, sensitization to relevant cues can trigger “wanting” and potentially lead
to addictive-like consumption.
Reactivity in brain regions associated with reward appraisal like the striatum,
amygdala, and OFC may be indicative of the incentive salience for drug and food
cues, where increased salience is associated with propensities for obesity and unsuc-
cessful abstinence in addictive disorders (Tang et al., 2012). In support, elevated
striatal response to monetary reward related prospectively to substance-use onset
over a 1-year follow-up (Stice et al., 2013b) and elevated responsivity of reward re-
gions (striatum, amygdala, OFC) to palatable food images (Demos et al., 2012), pal-
atable food commercials (Yokum et al., 2014), cues that predict palatable food image
presentation (Yokum et al., 2011), and palatable food receipt (Geha et al., 2013) re-
lated prospectively to future weight gain. Further, individual differences observed in
animal models provide insight to certain characteristics that may predict who will
sensitize to food cues. Individuals who exhibit greater motivation to engage with
cues that predict a drug or food reward, an indication of increased incentive salience
(so-called sign trackers), than to elements of reward receipt like the location of re-
ward delivery (so-called goal trackers) appear to be at greater risk for sensitization
(Flagel et al., 2009). Thus, while sensitization appears to contribute to continued
overconsumption of palatable foods, greater engagement with food-predictive cues
may predict which individuals will sensitize.
It has also been hypothesized that a reward deficiency may predispose some in-
dividuals to develop compulsive overeating or drug-taking behavior (Blum et al.,
2014). In some forms of obesity and addictive disorders, individuals may be moti-
vated to consume highly palatable food or drugs of abuse to compensate for dimin-
ished DA receptor availability (Koob and Le Moal, 2001). Consistent with the
reward deficiency theory, adults with versus without alcohol, cocaine, heroin, and
methamphetamine dependence show reduced striatal D2-like receptor availability
and sensitivity (Volkow et al., 2001; Wang et al., 1997) and lower D2-like receptor
density may increase risk for relapse after treatment (Heinz et al., 2004). Further, low
striatal D2-like receptor availability in primates relates prospectively to increased
future drug self-administration (Nader et al., 2006). Likewise, obese versus lean
adults show lower striatal DA D2-like receptor availability (de Weijer et al.,
2011; Volkow et al., 2008), although two other studies found no significant group
differences (Eisenstein et al., 2013; Haltia et al., 2007), with differences across stud-
ies possibly attributable to small sample sizes, differences in degrees of obesity, dif-
ferent radioligands used, or other factors. Obese versus lean adults show lower
capacity of nigrostriatal neurons to synthesize DA (Wilcox et al., 2009) and less
striatal responsivity to tastes of high-fat/sugar beverages (Babbs et al., 2013; Stice
et al., 2008). Obese versus lean rats likewise have lower basal DA levels and
D2-like receptor availability and less ex vivo DA release in response to electrical
stimulation in the nucleus accumbens and dorsal striatum (Geiger et al., 2009;
Thanos et al., 2008).
It is unknown whether hypoactivation in reward circuitry in response to acute ad-
ministration may be a cause or consequence in either addictive disorders or obesity as
prolonged overconsumption of drugs and rewarding food may decrease striatal DA
availability. Animal experiments show that regular substance use reduces striatal
D2-like receptors (Nader et al., 2006) and sensitivity of reward circuitry (Kenny
et al., 2006), and humans with cocaine abuse show blunted DA release in response
3 Shared neural systems: impulsivity 333
to stimulant drugs relative to nonaddicted comparison subjects (Volkow et al., 2005)

and tolerance to the euphoric effects of cocaine (O’Brien et al., 2006). Chronic co-
caine use has been associated with downregulated dopaminergic responses to both
cocaine and food cues (Tomasi et al., 2015). These data imply that substance use
contributes to the downregulated reward circuitry observed in the cross-sectional
studies. Similarly, prospective human (Stice et al., 2010a) and experimental animal
studies (Geiger et al., 2009; Johnson and Kenny, 2010; Thanos et al., 2008) indicate
that overeating may contribute to reward region hyporesponsivity during food con-
sumption. Further, studies have suggested that individuals vulnerable to substance
use (Stice et al., 2013b) and obesity (Stice et al., 2011; Verbeken et al., 2012)
may initially exhibit hyperresponsiveness in reward-related brain regions to rewards
in general. This hyperresponsiveness may increase motivation to seek out highly re-
warding, palatable foods and these individuals may appear to be hyporesponsive to
reward after neuroplastic changes associated with chronic overeating behavior have
occurred.
3 SHARED NEURAL SYSTEMS: IMPULSIVITY

Another domain implicated in both obesity and addictive disorders is an executive-
control deficiency, often evident by impulsive behavior. Obese individuals and per-
sons with addictions appear to favor short-term rewards of food or drug instead of
long-term health benefits (e.g., weight reduction in obesity; Mole et al., 2014). In
decision-making tasks, obese women not only make more impulsive decisions than
healthy women (Davis et al., 2010), but also exhibit decreased activation in
executive-control brain regions (e.g., middle frontal gyri, medial prefrontal cortex
[PFC]) during decision-making processes (Kishinevsky et al., 2012; Stoeckel
et al., 2013). Similar patterns of impulsive decision-making coupled with diminished
activation in executive-control regions have also been observed in addictive disor-
ders (MacKillop et al., 2011), and decreased inhibitory-control activation may be
predictive of relapse (Paulus et al., 2005). Similarly, Kishinevsky and colleagues
(2012) observed that diminished activity in executive-control structures related to
future weight gain.
One proposed explanation for this potentially maladaptive decision-making
process is abnormal striato-cortical connectivity similarly observed in addictive
disorders (Hanlon et al., 2011; Liu et al., 2009) and obesity (Garcia-Garcia et al.,
2013; Tomasi and Volkow, 2013). In this dysfunctional connection, brain structures
implicated in reward appraisal (e.g., OFC, ventromedial PFC) may be capable of
overwhelming inhibitory-control regions (e.g., dorsolateral PFC) to result in impul-
sive decision-making (Weygandt et al., 2013; Zhang et al., 2015). Additionally, re-
cent studies observed lower brain volumes in the OFC in obese women (Shott et al.,
2014) and a lack of synchronicity between the OFC and PFC in fasted obese men
(Zhang et al., 2015), providing further evidence that diminished inhibitory control
may lead to overeating in obesity (Zhang et al., 2015) in a manner akin to compulsive
drug-taking in addictive disorders (Ma et al., 2010). For some obese individuals, food
cues may activate regions associated with reward salience, and the executive-control
neural system may be inefficient at suppressing the drive to seek certain foods.
Though neuroimaging research should continue to examine deficits in striato-
cortical connectivity in obesity, it appears likely that deficits in executive-control
neural circuitry may similarly contribute to impulsive decision-making in obesity
and addiction.
4 SHARED NEURAL SYSTEMS: EMOTION DYSREGULATION

In both addiction and obesity, neural systems underlying emotion-regulation pro-
cesses seem to be impaired. Strong emotional states frequently precipitate drug
use and overeating behavior, which may suggest that some individuals utilize
addictive substances and highly palatable foods to compensate for deficient
emotion-regulation processes (Singh, 2014; Sinha and Jastreboff, 2013). Notably,
existing research has observed that humans typically consume foods high in fat
and/or refined carbohydrates in response to emotional states like stress or negative
affect, which may be particularly relevant for the development of obesity (Morris
et al., 2014).
Similar to addictive disorders, negative affect appears to implicate neural systems
associated with increased craving and compulsive consumption in obesity (Sinha and
Jastreboff, 2013). Jastreboff and colleagues (2013) found that obese, compared to
lean, individuals exhibited greater activity in striatal regions when exposed to stress
and highly palatable food cues, relative to neutral-relaxing cues, and increased ac-
tivation of the dorsal striatum in response to stress and food cues was related to stron-
ger food cravings. This suggests that emotional states may activate brain regions
associated with habitual behavior, like the dorsal striatum, which motivates certain
obese individuals to consume highly palatable foods (Jastreboff et al., 2013).
Coupled with increased activation in reward motivation structures, Tryon et al.
(2013) observed that chronic stress was associated with less prefrontal activation
in response to high-calorie food cues, and this pattern of activation related to greater
consumption of high-calorie foods. Collectively, it appears that emotional states may
be related to neural activation subserving increased craving and diminished inhibi-
tory control in obesity, which is also observed in addictive disorders (Sinha, 2008).
5 SUMMARY OF SHARED NEURAL SYSTEMS

Overlapping neural systems appear to be implicated in both obesity and addictive
disorders, including reward dysfunction, executive-control deficiencies, and emo-
tion regulation. The existing neuroimaging data suggests that addictive-like mech-
anisms may contribute to obesity for some individuals. Thus, exploration of the
6 Differences between obesity and addictive disorders 335
“food addiction” construct may be clinically useful for understanding overeating be-
havior and informing intervention approaches for certain individuals with obesity.
6 DIFFERENCES BETWEEN OBESITY AND ADDICTIVE

DISORDERS
While existing neuroimaging studies have observed similarities between obesity and
substance-use disorders, important differences exist between “food addiction” and
traditional addictive disorders. Notably, food is necessary for survival. However,
many highly palatable foods are not in their natural state and have instead been pro-
cessed with added amounts of potentially rewarding ingredients like fat and refined
carbohydrates (Gearhardt et al., 2011a). Similar to the word “drug” which includes
addictive (e.g., cocaine) and nonaddictive (e.g., aspirin) substances, future research
is warranted to examine whether foods in a natural state (e.g., banana) are equally
implicated in problematic, addictive-like eating behavior as highly processed foods
(e.g., pizza).
Similarly, the current conceptualization of “food addiction” differs from traditional
addictive disorders because an addictive agent in certain foods and the “dose” that may
increase certain foods’ addictive potential has not been investigated (Ziauddeen and
Fletcher, 2013). For drugs of abuse, an addictive agent has been defined (e.g., ethanol
in alcohol, nicotine in cigarettes) and high concentrations of those ingredients are
linked to an increased addictive potential (Henningfield and Keenan, 1993). In con-
trast, although highly processed foods have been hypothesized to be most likely im-
plicated in addictive-like eating due to high levels of fat and/or refined carbohydrates
(Gearhardt et al., 2011a), it has not been examined whether specific food attributes
(e.g., sugar content) may be capable of triggering an addictive-like response in certain
individuals; however, there are preliminary data suggesting that sugar more effectively
recruits reward and gustatory regions compared to fat (Stice et al., 2013a). Addition-
ally, no previous research has evaluated whether a particular “dose” or quantity of the
“addictive” food attribute would increase the abuse potential of an “addictive” food
(Ziauddeen et al., 2012). For example, if future studies indicate that sugar may be im-
plicated in “food addiction,” a threshold may be set to describe the concentration of
sugar that significantly elevates a food’s addictive potential (e.g., 30% calories from
sugar). Further, specific sugars may differentially elicit brain responses that may as-
sociate differentially with appetite and reward pathways and lead to addictive patterns
of eating (Page et al., 2013). However, unlike drugs of abuse, certain foods may have
multiple addictive agents, like fat and sugar, which may both increase the food’s ad-
dictive potential, but perhaps through different mechanisms.
Another difference that may exist between “food addiction” and substance-use
disorders is the presentation of withdrawal symptoms. Although limited, preclinical
literature suggests that dieters may experience headaches and psychological preoc-
cupation with food (Gearhardt et al., 2009a), but it is unlikely that individuals with
“food addiction” would experience severe, life-threatening physiological withdrawal
symptoms if highly processed foods were removed from their diet (Ziauddeen et al.,
2012). Consequently, “food addiction” may vary from traditional addictive disorders
like opioid-dependence that produce acute physiological withdrawal symptoms,
such as vomiting and sweating. On the other hand, removing certain foods from
the diet may be more likely to trigger psychological withdrawal symptoms like anx-
iety. Such psychological features are experienced by a subset of individuals with
pathological gambling (or gambling disorder) and are included in a withdrawal-
related inclusionary criterion for the condition (American Psychiatric Association,
2013). Although withdrawal appears to manifest differently across addictive disor-
ders, no previous research has examined whether withdrawal symptoms involving
psychological states may contribute to addictive-like eating behavior.
Although “food addiction” is less likely to be associated with life-threatening with-
drawal symptoms, there may be severe risks associated with “food addiction” that are
not relevant in substance-use disorders. Unlike substance-use disorders, many individ-
uals are exposed to highly processed foods within the first year of life (Fox et al., 2004).
If certain foods have addictive potential, exposure to these foods during critical devel-
opmental periods may contribute to the onset of persistent, lifelong obesity for some
people (Epstein et al., 1985). Unlike drugs of abuse that are illegal, expensive, or age-
restricted, highly processed foods are easily accessible and affordable in our modern
food environment. In this respect, “food addiction” may be considered a greater threat
than substance-use disorders because there are fewer societal restrictions on the con-
sumption of highly processed foods. Thus, while “food addiction” may not be associ-
ated with severe physiological withdrawal, it may pose a unique risk in infancy and
childhood due to early first exposure that may increase its severity.
7 DIFFERENCES BETWEEN ADDICTIVE DISORDERS

Though premature acceptance of “food addiction” has been cautioned against due to
inconsistencies with other addictive disorders (Ziauddeen and Fletcher, 2013;
Ziauddeen et al., 2012), it is important to note differences that exist among addictive
disorders included in the DSM-5 (American Psychiatric Association, 2013). Notably,
the characteristics required for a substance to be considered addictive have changed
over time. As previously mentioned, alcohol and opioid dependence may trigger in-
tense physiological withdrawal symptoms (Leshner, 1997; Skinner and Allen, 1982),
whereas cocaine and nicotine dependence appear more likely to produce psycholog-
ical symptoms like involving anxiety and irritability (Brower and Paredes, 1987;
Weddington et al., 1990). Additionally, the inclusion of the behavioral addiction
gambling disorder in the DSM-5 reflects a shift away from physiological withdrawal
as a necessary component of addiction (American Psychiatric Association, 2013).
Importantly, regardless of whether the symptoms are physical or psychological,
the experience of withdrawal appears to increase the probability of relapse across
addictive disorders (Kenford et al., 2002; Ray, 1961). Thus, a key, shared component
of withdrawal within addiction may involve the increased chance of relapse associ-
ated with experiencing withdrawal symptoms. In this respect, it will be important for
8 Future directions in food addiction research 337
future research to examine whether individuals with “food addiction” experience

withdrawal symptoms that may trigger addictive-like eating behavior.
Another difference that exists within addictive disorders is the experience of in-
toxication. Some drugs of abuse, such as heroin, may result in intoxication where the
individual enters a mind-altered state and may behave recklessly or break the law
(Inciardi, 1979). Other examples of heroin intoxication symptoms are unpredictable
mood swings, risky behavior, and breathing problems. However, other substances
like nicotine may not trigger similar intoxication symptoms and allow individuals
to function while using the drug. For example, it is often legal to smoke cigarettes
while at work or operating a vehicle. Although nicotine does not produce acute neg-
ative consequences due to intoxication in the same way heroin does, prolonged nic-
otine use often leads to long-term negative health consequences like coronary heart
disease, stroke, lung cancer, and emphysema (US Surgeon General, 1982). In behav-
ioral addictions like pathological gambling or gambling disorder, the negative con-
sequences may not manifest in acute intoxication, but rather in long-term outcomes
like loss of money and familial stress. Similarly, while certain foods are likely inca-
pable of triggering intoxication, long-term negative consequences may be associated
with chronic addictive-like eating behavior, such as obesity, heart disease, and dia-
betes (Bray, 2004). In summary, while addictions vary in their degree of intoxication,
individuals with addictive disorders share a characteristic of continued behavioral
engagement in the addictive process despite negative consequences.
If certain foods are identified as “addictive,” it is unlikely that all individuals who
consume these foods will develop addictive-like eating behavior. In traditional addic-
tive disorders, a small fraction of individuals who use addictive substances or engage
in addictive behaviors develop dependence (Anthony et al., 1994). Applying this logic
to addictive-like eating behavior, it would follow that only a subset of individuals who
are exposed to potentially “addictive” foods would later develop “food addiction.”
Additionally, overconsumption of “addictive” foods would likely not lead to
addictive-like eating behavior for all individuals. This is similarly observed in addic-
tive disorders, where a larger percentage of individuals overconsume drugs of abuse
than develop dependence (Dawson et al., 2004; Hasin et al., 2007). Further, it is
unlikely that clinically significant symptoms of addictive-like eating would occur
exclusively in obesity, and symptoms have been observed across a range of body mass
indexes (Gearhardt et al., 2011c). Thus, subtyping may be one fruitful avenue that
emerges from examining whether an addiction perspective can be applied to problem-
atic eating behavior for some individuals. This may increase the efficacy of treatment
and prevention efforts for obesity and for disordered eating more generally.
8 FUTURE DIRECTIONS IN FOOD ADDICTION RESEARCH

One important gap in the existing literature on “food addiction” is the examination of
which foods are most likely associated with addictive-like eating. An addiction
framework suggests that an addictive agent in some foods would interact with indi-
vidual vulnerabilities to result in “food addiction.” It follows that identifying whether
certain foods or food attributes (e.g., specific sugars) may be capable of triggering an
addictive-like process is essential to evaluating this perspective. Further, a drug of
abuse has a greater addictive potential when a high “dose” of an addictive agent
is rapidly absorbed by the system (Verebey and Gold, 1988). In our modern food
environment, many highly processed foods contain added fat and/or refined carbo-
hydrates (like white flour and sugar) in quantities exceeding what is found in natu-
rally occurring foods. Akin to addictive disorders, the way in which these ingredients
are absorbed in the body may also contribute to a food’s addictive potential. Foods
that have been processed by adding fat and/or refined carbohydrates while simulta-
neously stripping nutrients that slow digestion, like fiber and water, may have an el-
evated addictive potential. For example, a highly processed food, like chocolate
cake, with added amounts of fat and rapidly absorbed refined carbohydrates may
be expected to have a greater addictive potential than an apple, which contains nat-
ural sugars, but fiber and water to slow digestion. In highly processed foods, the in-
creased concentration of rewarding ingredients coupled with the rapid rate that
refined carbohydrates are absorbed may contribute to an increased abuse potential.
In support, Schulte et al. (2015) found that highly processed foods were most likely to
be associated with addictive-like eating behaviors, particularly for individuals who
endorsed symptoms of “food addiction.” Future studies should examine whether
these highly processed foods are capable of producing neuroplastic changes in the
brain, akin to those associated with consumption of drugs of abuse. Demonstrating
that certain foods are capable of changing neural systems in a similar manner as ad-
dictive substances would provide further support for the validity and unique explan-
atory power of “food addiction” for some individuals with obesity.
A potential avenue to investigate how certain foods may change reward-related
circuitry may involve examining neural mechanisms across the lifespan. Interest-
ingly, childhood-onset obesity typically persists into adulthood (Epstein et al.,
1985). Similarly substance-use disorders that emerge during early adolescence also
often last throughout one’s life (Chen et al., 2009). One potential explanation is that
similar changes in reward mechanisms may be occurring, resulting in chronic addic-
tive responses. While hypoactive reward-responsiveness may motivate obese indi-
viduals to seek highly rewarding food in adulthood (Blum et al., 2006), recent
research has suggested that obese children actually exhibit greater functional connec-
tivity between reward-related brain regions, including the left lateral OFC, and
executive-control structures, such as the left ventromedial prefrontal cortex
(Black et al., 2014). Increased input from reward neural systems to regions of
cognitive control may make obese children particularly responsive to food cues
(Bruce et al., 2010). However, no previous studies have examined reward-related
neural mechanisms in infancy that may predispose certain individuals to become
obese as children. Given the existing literature, it is uncertain whether increased
functional connectivity between reward and executive-control regions may represent
a cause or consequence of obesity in children. This is an essential area to explore,
since children are exposed to highly rewarding food at young ages. If certain foods
may be associated with addictive-like eating behaviors, it is possible that marketing
Acknowledgments 339
restrictions may help decrease potential risks that some children have to develop
“food addiction” and persistent obesity.
Finally, applying an addiction perspective to problematic eating behavior for
some obese individuals may increase treatment options and efficacy. Behavioral
treatments for addictive disorders that focus on craving management and relapse pre-
vention may be adapted for the treatment of addictive-like eating behaviors. Phar-
macological approaches may also be relevant. For example, naltrexone and
buproprion, which are used for the treatment of addictive disorders, also appear to
be a successful intervention technique for obesity (Greenway et al., 2010). Addition-
ally, neurobiological treatments, such as neurofeedback, have recently been explored
as a treatment method for substance-use disorders. This technique uses real-time
fMRI (rtfMRI) feedback to help individuals reduce cue-induced craving (Sokunbi
et al., 2014). For example, individuals are first shown a substance-relevant cue
(e.g., cigarette) and receive feedback about increased brain activity in regions asso-
ciated with craving, like the ACC. Next, the patient is asked to reduce activity in this
region and self-report craving for the substance. The existing literature suggests that
neurofeedback may be an effective technique for reducing craving for addictive sub-
stances, including nicotine (Li et al., 2013) and opiates (Dehghani-Arani et al., 2013).
Since craving appears to be implicated in both substance-use disorders and “food
addiction,” neurofeedback may be a useful treatment tool for obese individuals
reporting addictive-like eating behavior.
9 CONCLUDING REMARKS
Obesity appears to share common neural systems with traditional addictive disor-
ders, suggesting that an addictive-like process may contribute to problematic eating
behavior for some obese individuals. If certain foods are identified as “addictive,”
treatment and prevention efforts that adopt an addiction framework would likely
be efficacious for the subtype of obese individuals endorsing “food addiction.” How-
ever, future research is needed to determine whether an addiction perspective is clin-
ically useful to explain some forms of obesity. Important next directions may involve
investigating if certain foods can produce neuroplastic changes in the brain, charac-
terizing the potentially addictive agents in these foods, looking longitudinally at
changes in reward mechanisms, and examining whether treatments developed for
drug addiction translate to effective interventions for food addiction.
ACKNOWLEDGMENTS
This was supported by P20 DA027844, CASAColumbia and the National Center for Respon-
sible Gaming.
Disclosures: The authors report that they have no financial conflicts of interest with respect
to the content of this manuscript. Dr. Potenza has received financial support or compensation
for the following: Dr. Potenza has consulted for and advised Somaxon, Boehringer Ingelheim,
Lundbeck, Ironwood, Shire, INSYS and RiverMend Health; has received research support
from the National Institutes of Health, Veteran’s Administration, Mohegan Sun Casino,
the National Center for Responsible Gaming, and Forest Laboratories, Ortho-McNeil,
Oy-Control/Biotie, Glaxo-SmithKline, Pfizer, and Psyadon pharmaceuticals; has participated
in surveys, mailings or telephone consultations related to drug addiction, impulse control dis-
orders or other health topics; has consulted for gambling entities, law offices and the federal
public defender’s office in issues related to impulse control disorders; provides clinical care in
the Connecticut Department of Mental Health and Addiction Services Problem Gambling Ser-
vices Program; has performed grant reviews for the National Institutes of Health and other
agencies; has edited or guest-edited journals or journal sections; has given academic lectures
in grand rounds, CME events and other clinical or scientific venues; and has generated books
or book chapters for publishers of mental health texts.
REFERENCES
American Psychiatric Association, Diagnostic and statistical manual of mental disorders:
DSM-5. http://dsm.psychiatryonline.org/book.aspx?bookid¼556%3E. Available from.
Anthony, J.C., Warner, L.A., Kessler, R.C., 1994. Comparative epidemiology of dependence
on tobacco, alcohol, controlled substances, and inhalants: basic findings from the national
comorbidity survey. Exp. Clin. Psychopharmacol. 2 (3), 244–268.
Avena, N.M., Rada, P., Hoebel, B.G., 2009. Sugar and fat bingeing have notable differences in
addictive-like behavior. J. nutr. 139 (3), 623–628.
Babbs, R.K., Sun, X., Felsted, J., Chouinard-Decorte, F., Veldhuizen, M.G., Small, D.M.,
2013. Decreased caudate response to milkshake is associated with higher body mass index
and greater impulsivity. Physiol. Behav. 121, 103–111.
Berridge, K.C., 2009. ‘Liking’ and ‘wanting’ food rewards: brain substrates and roles in eating
disorders. Physiol. Behav. 97 (5), 537–550.
Black, W.R., Lepping, R.J., Bruce, A.S., Powell, J.N., Bruce, J.M., Martin, L.E., Davis, A.M.,
Brooks, W.M., Savage, C.R., Simmons, W.K., 2014. Tonic hyper-connectivity of reward
neurocircuitry in obese children. Obesity (Silver Spring) 22 (7), 1590–1593.
Blum, K., Chen, T.J., Meshkin, B., Downs, B.W., Gordon, C.A., Blum, S., Mengucci, J.F.,
Braverman, E.R., Arcuri, V., Varshavskiy, M., Deutsch, R., Martinez-Pons, M., 2006. Re-
ward deficiency syndrome in obesity: a preliminary cross-sectional trial with a Genotrim
variant. Adv. Ther. 23 (6), 1040–1051.
Blum, K., Thanos, P.K., Gold, M.S., 2014. Dopamine and glucose, obesity, and reward defi-
ciency syndrome. Front. Psychol. 5, 919.
Bray, G.A., 2004. Medical consequences of obesity. J. Clin. Endocrinol. Metab. 89 (6),
2583–2589.
Brower, K.J., Paredes, A., 1987. Cocaine withdrawal. Arch. Gen. Psychiatry 44 (3), 297–298.
Bruce, A.S., Holsen, L.M., Chambers, R.J., Martin, L.E., Brooks, W.M., Zarcone, J.R.,
Butler, M.G., Savage, C.R., 2010. Obese children show hyperactivation to food pictures
in brain networks linked to motivation, reward and cognitive control. Int. J. Obes. (Lond)
34 (10), 1494–1500.
Burger, K.S., Stice, E., 2013. Elevated energy intake is correlated with hyperresponsivity in
attentional, gustatory, and reward brain regions while anticipating palatable food receipt.
Am. J. Clin. Nutr. 97 (6), 1188–1194.
References 341
Chen, C.Y., Storr, C.L., Anthony, J.C., 2009. Early-onset drug use and risk for drug depen-
dence problems. Addict. Behav. 34 (3), 319–322.
Davis, C., Patte, K., Curtis, C., Reid, C., 2010. Immediate pleasures and future consequences.
A neuropsychological study of binge eating and obesity. Appetite 54 (1), 208–213.
Dawson, D.A., Grant, B.F., Stinson, F.S., Chou, P.S., 2004. Toward the attainment of low-risk
drinking goals: a 10-year progress report. Alcohol. Clin. Exp. Res. 28 (9), 1371–1378.
Dehghani-Arani, F., Rostami, R., Nadali, H., 2013. Neurofeedback training for opiate addic-
tion: improvement of mental health and craving. Appl. Psychophysiol. Biofeedback 38 (2),
133–141.
Demos, K.E., Heatherton, T.F., Kelley, W.M., 2012. Individual differences in nucleus accum-
bens activity to food and sexual images predict weight gain and sexual behavior.
J. Neurosci. 32 (16), 5549–5552.
de Weijer, B.A., van de Giessen, E., van Amelsvoort, T.A., Boot, E., Braak, B., Janssen, I.M.,
van de Laar, A., Fliers, E., Serlie, M.J., Booij, J., 2011. Lower striatal dopamine D2/3
receptor availability in obese compared with non-obese subjects. EJNMMI Res. 1 (1), 37.
Due, D.L., Huettel, S.A., Hall, W.G., Rubin, D.C., 2002. Activation in mesolimbic and visuo-
spatial neural circuits elicited by smoking cues: evidence from functional magnetic reso-
nance imaging. Am. J. Psychiatry 159 (6), 954–960.
Eisenstein, S.A., Antenor-Dorsey, J.A., Gredysa, D.M., Koller, J.M., Bihun, E.C., Ranck, S.A.,
Arbelaez, A.M., Klein, S., Perlmutter, J.S., Moerlein, S.M., Black, K.J., Hershey, T., 2013.
A comparison of D2 receptor specific binding in obese and normal-weight individuals
using PET with (N-[(11)C]methyl)benperidol. Synapse 67 (11), 748–756.
Epstein, L.H., Wing, R.R., Valoski, A., 1985. Childhood obesity. Pediatr. Clin. North Am.
32 (2), 363–379.
actions to habits to compulsion. Nat. Neurosci. 8 (11), 1481–1489.
Ferreira, J.G., Tellez, L.A., Ren, X., Yeckel, C.W., de Araujo, I.E., 2012. Regulation of fat
intake in the absence of flavour signalling. J. physiolog. 590 (4), 953–972.
Flagel, S.B., Akil, H., Robinson, T.E., 2009. Individual differences in the attribution of incen-
tive salience to reward-related cues: implications for addiction. Neuropharmacology
56 (Suppl 1), 139–148.
Fox, M.K., Pac, S., Devaney, B., Jankowski, L., 2004. Feeding infants and toddlers study: what
foods are infants and toddlers eating? J. Am. Diet. Assoc. 104, 22–30.
Garcia-Garcia, I., Jurado, M.A., Garolera, M., Segura, B., Sala-Llonch, R., Marques-Iturria, I.,
Pueyo, R., Sender-Palacios, M.J., Vernet-Vernet, M., Narberhaus, A., Ariza, M.,
Junque, C., 2013. Alterations of the salience network in obesity: a resting-state fMRI
study. Hum. Brain Mapp. 34 (11), 2786–2797.
Gearhardt, A.N., Corbin, W.R., Brownell, K.D., 2009a. Food addiction: an examination of the
diagnostic criteria for dependence. J. Addict. Med. 3 (1), 1–7.
Gearhardt, A.N., Corbin, W.R., Brownell, K.D., 2009b. Preliminary validation of the Yale
Food Addiction Scale. Appetite 52 (2), 430–436.
Gearhardt, A.N., Davis, C., Kuschner, R., Brownell, K.D., 2011a. The addiction potential of
hyperpalatable foods. Curr. Drug Abuse Rev. 4 (3), 140–145.
Gearhardt, A.N., White, M.A., Potenza, M.N., 2011b. Binge eating disorder and food addic-
tion. Curr. Drug Abuse Rev. 4 (3), 201–207.
Gearhardt, A.N., Yokum, S., Orr, P.T., Stice, E., Corbin, W.R., Brownell, K.D., 2011c. Neural
correlates of food addiction. Arch. Gen. Psychiatry 68 (8), 808–816.
Geha, P.Y., Aschenbrenner, K., Felsted, J., O’Malley, S.S., Small, D.M., 2013. Altered hypo-
thalamic response to food in smokers. Am. J. Clin. Nutr. 97 (1), 15–22.
Geiger, B.M., Haburcak, M., Avena, N.M., Moyer, M.C., Hoebel, B.G., Pothos, E.N., 2009.
Deficits of mesolimbic dopamine neurotransmission in rat dietary obesity. Neuroscience
159 (4), 1193–1199.
Greenway, F.L., Fujioka, K., Plodkowski, R.A., Mudaliar, S., Guttadauria, M., Erickson, J.,
Kim, D.D., Dunayevich, E., C-IS Group, 2010. Effect of naltrexone plus bupropion on
weight loss in overweight and obese adults (COR-I): a multicentre, randomised,
double-blind, placebo-controlled, phase 3 trial. Lancet 376 (9741), 595–605.
Haltia, L.T., Rinne, J.O., Merisaari, H., Maguire, R.P., Savontaus, E., Helin, S., Nagren, K.,
Kaasinen, V., 2007. Effects of intravenous glucose on dopaminergic function in the human
brain in vivo. Synapse 61 (9), 748–756.
Hanlon, C.A., Wesley, M.J., Stapleton, J.R., Laurienti, P.J., Porrino, L.J., 2011. The associa-
tion between frontal–striatal connectivity and sensorimotor control in cocaine users. Drug
Alcohol Depend. 115 (3), 240–243.
Hasin, D.S., Stinson, F.S., Ogburn, E., Grant, B.F., 2007. Prevalence, correlates, disability, and
comorbidity of DSM-IV alcohol abuse and dependence in the united states: results from
the national epidemiologic survey on alcohol and related conditions. Arch. Gen. Psychi-
atry 64 (7), 830–842.
Heinz, A., Siessmeier, T., Wrase, J., Hermann, D., Klein, S., Grüsser-Sinopoli, S.M., Flor, H.,
Braus, D.F., Buchholz, H.G., Gründer, G., et al., 2004. Correlation between dopamine D2
receptors in the ventral striatum and central processing of alcohol cues and craving. Am. J.
Psychiatry 161 (10), 1783–1789.
Henningfield, J.E., Keenan, R.M., 1993. Nicotine delivery kinetics and abuse liability.
J. Consult. Clin. Psychol. 61 (5), 743–750.
Inciardi, J.A., 1979. Heroin use and street crime. Crime Delinq. 25 (3), 335–346.
Jastreboff, A.M., Sinha, R., Lacadie, C., Small, D.M., Sherwin, R.S., Potenza, M.N., 2013.
Neural correlates of stress- and food cue-induced food craving in obesity: association with
insulin levels. Diabetes Care 36 (2), 394–402.
Johnson, P.M., Kenny, P.J., 2010. Dopamine D2 receptors in addiction-like reward dysfunc-
tion and compulsive eating in obese rats. Nat. Neurosci. 13 (5), 635–641.
Kalivas, P.W., O’Brien, C., 2008. Drug addiction as a pathology of staged neuroplasticity.
Kenford, S.L., Smith, S.S., Wetter, D.W., Jorenby, D.E., Fiore, M.C., Baker, T.B., 2002. Pre-
dicting relapse back to smoking: contrasting affective and physical models of dependence.
J. Consult. Clin. Psychol. 70 (1), 216–227.
Kenny, P.J., Chen, S.A., Kitamura, O., Markou, A., Koob, G.F., 2006. Conditioned withdrawal
drives heroin consumption and decreases reward sensitivity. J. Neurosci. 26 (22),
5894–5900.
Kishinevsky, F.I., Cox, J.E., Murdaugh, D.L., Stoeckel, L.E., Cook 3rd, E.W., Weller, R.E.,
2012. fMRI reactivity on a delay discounting task predicts weight gain in obese women.
Appetite 58 (2), 582–592.
Koob, G.F., Le Moal, M., 2001. Drug addiction, dysregulation of reward, and allostasis.
Lawrence, N.S., Hinton, E.C., Parkinson, J.A., Lawrence, A.D., 2012. Nucleus accumbens
response to food cues predicts subsequent snack consumption in women and increased
body mass index in those with reduced self-control. Neuroimage 63 (1), 415–422.
Leshner, A.I., 1997. Addiction is a brain disease, and it matters. Science 278 (5335), 45–47.
Li, X., Hartwell, K.J., Borckardt, J., Prisciandaro, J.J., Saladin, M.E., Morgan, P.S.,
Johnson, K.A., Lematty, T., Brady, K.T., George, M.S., 2013. Volitional reduction of
References 343
anterior cingulate cortex activity produces decreased cue craving in smoking cessation: a
preliminary real-time fMRI study. Addict. Biol. 18 (4), 739–748.
Liu, J., Liang, J., Qin, W., Tian, J., Yuan, K., Bai, L., Zhang, Y., Wang, W., Wang, Y., Li, Q.,
Zhao, L., Lu, L., von Deneen, K.M., Liu, Y., Gold, M.S., 2009. Dysfunctional connectivity
patterns in chronic heroin users: an fMRI study. Neurosci. Lett. 460 (1), 72–77.
Ma, N., Liu, Y., Li, N., Wang, C.X., Zhang, H., Jiang, X.F., Xu, H.S., Fu, X.M., Hu, X.,
Zhang, D.R., 2010. Addiction related alteration in resting-state brain connectivity.
Neuroimage 49 (1), 738–744.
MacKillop, J., Amlung, M.T., Few, L.R., Ray, L.A., Sweet, L.H., Munafo, M.R., 2011.
Delayed reward discounting and addictive behavior: a meta-analysis. Psychopharmacol-
ogy (Berl) 216 (3), 305–321.
Martin, L.E., Holsen, L.M., Chambers, R.J., Bruce, A.S., Brooks, W.M., Zarcone, J.R.,
Butler, M.G., Savage, C.R., 2010. Neural mechanisms associated with food motivation
in obese and healthy weight adults. Obesity (Silver Spring) 18 (2), 254–260.
Mole, T.B., Irvine, M.A., Worbe, Y., Collins, P., Mitchell, S.P., Bolton, S., Harrison, N.A.,
Robbins, T.W., Voon, V., 2014. Impulsivity in disorders of food and drug misuse. Psychol.
Med. 45, 771–782.
Morris, M.J., Beilharz, J., Maniam, J., Reichelt, A., Westbrook, R.F., 2014. Why is obesity
such a problem in the 21st century? The intersection of palatable food, cues and reward
pathways, stress, and cognition. Neurosci. Biobehav. Rev. In press.
Myrick, H., Anton, R.F., Li, X., Henderson, S., Drobes, D., Voronin, K., George, M.S., 2004.
Differential brain activity in alcoholics and social drinkers to alcohol cues: relationship to
craving. Neuropsychopharmacology 29 (2), 393–402.
Nader, M.A., Morgan, D., Gage, D.H., Nader, S.H., Calhoun, T.L., Buchheimer, N.,
Ehrenkaufer, R., Mach, R.H., 2006. PET imaging of dopamine D2 receptors during
chronic cocaine self-administration in monkeys. Nat. Neurosci. 9 (8), 1050–1056.
Ng, J., Stice, E., Yokum, S., Bohon, C., 2011. An fMRI study of obesity, food reward, and
perceived caloric density. Does a low-fat label make food less appealing? Appetite
57 (1), 65–72.
Nolan-Poupart, S., Veldhuizen, M.G., Geha, P., Small, D.M., 2013. Midbrain response to
milkshake correlates with ad libitum milkshake intake in the absence of hunger.
Appetite 60 (1), 168–174.
O’Brien, C.P., Volkow, N., Li, T.K., 2006. What’s in a word? Addiction versus dependence in
DSM-V. Am. J. Psychiatry 163 (5), 764–765.
Page, K.A., Chan, O., Arora, J., Belfort-Deaguiar, R., Dzuira, J., Roehmholdt, B., Cline, G.W.,
Naik, S., Sinha, R., Constable, R.T., Sherwin, R.S., 2013. Effects of fructose vs glucose on
regional cerebral blood flow in brain regions involved with appetite and reward pathways.
JAMA 309 (1), 63–70.
Gen. Psychiatry 62 (7), 761–768.
Ray, M.B., 1961. The cycle of abstinence and relapse among heroin addicts. Soc. Probl. 9 (2),
132–140.
sensitization theory of addiction. Brain Res. Brain Res. Rev. 18 (3), 247–291.
Schulte, E.M., Avena, N.M., Gearhardt, A.N., 2015. Which foods may be addictive? The roles
of processing, fat content, and glycemic load. PLoS One 10 (2), e0117959. http://dx.doi.
org/10.1371/journal.pone.0117959.
Shott, M.E., Cornier, M.A., Mittal, V.A., Pryor, T.L., Orr, J.M., Brown, M.S., Frank, G.K.,
2014. Orbitofrontal cortex volume and brain reward response in obesity. Int. J. Obes.
(Lond) 39, 214–221.
Singh, M., 2014. Mood, food, and obesity. Front. Psychol. 5, 925.
Sinha, R., 2008. Chronic stress drug use, and vulnerability to addiction. Ann. N. Y. Acad. Sci.
1141, 105–130.
Sinha, R., Jastreboff, A.M., 2013. Stress as a common risk factor for obesity and addiction.
Biol. Psychiatry 73 (9), 827–835.
Skinner, H.A., Allen, B.A., 1982. Alcohol dependence syndrome: measurement and valida-
tion. J. Abnorm. Psychol. 91 (3), 199–209.
Small, D.M., Jones-Gotman, M., Dagher, A., 2003. Feeding-induced dopamine release in dor-
sal striatum correlates with meal pleasantness ratings in healthy human volunteers. Neuro-
image 19 (4), 1709–1715.
Sokunbi, M.O., Linden, D.E., Habes, I., Johnston, S., Ihssen, N., 2014. Real-time fMRI brain-
computer interface: development of a “motivational feedback” subsystem for the regula-
tion of visual cue reactivity. Front. Behav. Neurosci. 8, 392.
Stice, E., Spoor, S., Bohon, C., Veldhuizen, M.G., Small, D.M., 2008. Relation of reward from
food intake and anticipated food intake to obesity: a functional magnetic resonance imag-
ing study. J. Abnorm. Psychol. 117 (4), 924–935.
Stice, E., Yokum, S., Blum, K., Bohon, C., 2010a. Weight gain is associated with reduced
striatal response to palatable food. J. Neurosci. 30 (39), 13105–13109.
Stice, E., Yokum, S., Bohon, C., Marti, N., Smolen, A., 2010b. Reward circuitry responsivity
to food predicts future increases in body mass: moderating effects of DRD2 and DRD4.
Neuroimage 50 (4), 1618–1625.
Stice, E., Yokum, S., Burger, K.S., Epstein, L.H., Small, D.M., 2011. Youth at risk for obesity
show greater activation of striatal and somatosensory regions to food. J. Neurosci. 31 (12),
4360–4366.
Stice, E., Burger, K.S., Yokum, S., 2013a. Relative ability of fat and sugar tastes to
activate reward, gustatory, and somatosensory regions. Am. J. Clin. Nutr. 98 (6),
1377–1384.
Stice, E., Yokum, S., Burger, K.S., 2013b. Elevated reward region responsivity predicts
future substance use onset but not overweight/obesity onset. Biol. Psychiatry 73 (9),
869–876.
Stoeckel, L.E., Murdaugh, D.L., Cox, J.E., Cook 3rd, E.W., Weller, R.E., 2013. Greater im-
pulsivity is associated with decreased brain activation in obese women during a delay dis-
counting task. Brain Imaging Behav. 7 (2), 116–128.
Tang, D.W., Fellows, L.K., Small, D.M., Dagher, A., 2012. Food and drug cues activate sim-
ilar brain regions: a meta-analysis of functional MRI studies. Physiol. Behav. 106 (3),
317–324.
Thanos, P.K., Michaelides, M., Piyis, Y.K., Wang, G.J., Volkow, N.D., 2008. Food restriction
markedly increases dopamine D2 receptor (D2R) in a rat model of obesity as assessed with
in-vivo muPET imaging ([11C] raclopride) and in-vitro ([3H] spiperone) autoradiography.
Synapse 62 (1), 50–61.
Tobler, P.N., Fiorillo, C.D., Schultz, W., 2005. Adaptive coding of reward value by dopamine
neurons. Science 307 (5715), 1642–1645.
Tomasi, D., Volkow, N.D., 2013. Striatocortical pathway dysfunction in addiction and obesity:
differences and similarities. Crit. Rev. Biochem. Mol. Biol. 48 (1), 1–19.
References 345
Tomasi, D., Wang, G.J., Wang, R., Caparelli, E.C., Logan, J., Volkow, N.D., 2015. Overlap-
ping patterns of brain activation to food and cocaine cues in cocaine abusers: association to
striatal D2/D3 receptors. Hum. Brain Mapp. 36 (1), 120–136.
Tryon, M.S., Carter, C.S., Decant, R., Laugero, K.D., 2013. Chronic stress exposure may affect
the brain’s response to high calorie food cues and predispose to obesogenic eating habits.
Physiol. Behav. 120, 233–242.
US Surgeon General, 1982. The Health Consequences of Smoking: Chronic Obstructive Lung
Disease. US Department of Health and Human Resources, Washington, DC.
Verbeken, S., Braet, C., Lammertyn, J., Goossens, L., Moens, E., 2012. How is reward sen-
sitivity related to bodyweight in children? Appetite 58 (2), 478–483.
Verebey, K., Gold, M.S., 1988. From coca leaves to crack: the effects of dose and routes of
administration in abuse liability. Psychiatr. Ann. 18 (9), 513–520.
Volkow, N.D., Chang, L., Wang, G.J., Fowler, J.S., Ding, Y.S., Sedler, M., Logan, J.,
Franceschi, D., Gatley, J., Hitzemann, R., Gifford, A., Wong, C., Pappas, N., 2001.
Low level of brain dopamine D2 receptors in methamphetamine abusers: association with
metabolism in the orbitofrontal cortex. Am. J. Psychiatry 158 (12), 2015–2021.
Volkow, N.D., Wang, G.J., Ma, Y., Fowler, J.S., Wong, C., Ding, Y.S., Hitzemann, R.,
Swanson, J.M., Kalivas, P., 2005. Activation of orbital and medial prefrontal cortex by
methylphenidate in cocaine-addicted subjects but not in controls: relevance to addiction.
J. Neurosci. 25 (15), 3932–3939.
Volkow, N.D., Wang, G.J., Telang, F., Fowler, J.S., Logan, J., Childress, A.R., Jayne, M.,
Ma, Y., Wong, C., 2006. Cocaine cues and dopamine in dorsal striatum: mechanism of
craving in cocaine addiction. J. Neurosci. 26 (24), 6583–6588.
Volkow, N.D., Wang, G.J., Telang, F., Fowler, J.S., Thanos, P.K., Logan, J., Alexoff, D.,
Ding, Y.S., Wong, C., Ma, Y., Pradhan, K., 2008. Low dopamine striatal D2 receptors
are associated with prefrontal metabolism in obese subjects: possible contributing factors.
Neuroimage 42 (4), 1537–1543.
Wang, G.J., Volkow, N.D., Fowler, J.S., Logan, J., Abumrad, N.N., Hitzemann, R.J.,
Pappas, N.S., Pascani, K., 1997. Dopamine D2 receptor availability in opiate-dependent
subjects before and after naloxone-precipitated withdrawal. Neuropsychopharmacology
16 (2), 174–182.
Wang, G.J., Volkow, N.D., Fowler, J.S., 2002. The role of dopamine in motivation for food in
humans: implications for obesity. Expert Opin. Ther. Targets 6 (5), 601–609.
Weddington, W.W., Brown, B.S., Haertzen, C.A., Cone, E.J., Dax, E.M., Herning, R.I.,
Michaelson, B.S., 1990. Changes in mood, craving, and sleep during short-term abstinence
reported by male cocaine addicts. A controlled, residential study. Arch. Gen. Psychiatry
47 (9), 861–868.
Weygandt, M., Mai, K., Dommes, E., Leupelt, V., Hackmack, K., Kahnt, T., Rothemund, Y.,
Spranger, J., Haynes, J.D., 2013. The role of neural impulse control mechanisms for die-
tary success in obesity. Neuroimage 83, 669–678.
Wilcox, C.E., Braskie, M.N., Kluth, J.T., Jagust, W.J., 2009. Overeating behavior and striatal
dopamine with 6-[F]-fluoro-L-m-tyrosine PET. J. Obes. 2010, 12–20.
Yokum, S., Ng, J., Stice, E., 2011. Attentional bias to food images associated with elevated
weight and future weight gain: an fMRI study. Obesity (Silver Spring) 19 (9), 1775–1783.
Yokum, S., Gearhardt, A.N., Harris, J.L., Brownell, K.D., Stice, E., 2014. Individual differ-
ences in striatum activity to food commercials predict weight gain in adolescents. Obesity
(Silver Spring) 22 (12), 2544–2551.
Zhang, B., Tian, D., Yu, C., Zhang, J., Tian, X., von Deneen, K.M., Zang, Y., Walter, M.,
Liu, Y., 2015. Altered baseline brain activities before food intake in obese men: a resting
state fMRI study. Neurosci. Lett. 584C, 156–161.
Ziauddeen, H., Fletcher, P.C., 2013. Is food addiction a valid and useful concept? Obes. Rev.
14 (1), 19–28.
Ziauddeen, H., Farooqi, I.S., Fletcher, P.C., 2012. Obesity and the brain: how convincing is the
addiction model? Nat. Rev. Neurosci. 13 (4), 279–286.
Index
Note: Page numbers followed by “f ” indicate figures, and “t” indicate tables.
A Addiction vulnerability, 3–4

A (asparagine) allele, 255, 256t behavioral traits, 4–5
Addiction medicine environmental factors and life experiences, 7–8
alcohol (see Alcohol) epigenetics, 6–7
drug-induced neurotoxicity genetic and environmental risk factors, 8
binge episodes, 31 genetics, 5–6
intoxicated patients during overdose, 31 neurobiological factors, 5
nontreatment seekers, 30 Addictive disorders
relapse-prone patients, 31 AB (see Attentional bias (AB))
severe drug withdrawal symptoms, 31 alcohol (see Alcohol)
treatment seekers, 30 brain regions, reactivity, 331–332
learning and memory chronic cocaine, 332–333
extinction, 99–100 DA, 330–331
reconsolidation, 98–99 D2-like receptor availability, 332
restoring goal-directed behavior, drug craving (see Drug craving)
100–101, 101f DSM-5, 336–337
nicotine emotion dysregulation, 334
cholinergic neurotransmission, 201–202 food addiction, 337–339
dopamine, 206, 207t functional magnetic resonance imaging, 331
endocannabinoid signaling, 206 gambling disorder, 312
endogenous opioid signaling, 205 behavioral treatment, 317
GABA neurotransmission, 204–205 DTI, 315
glutamate neurotransmission, 203–204 electrophysiology, 313
neurocircuitry, 193–201 fMRI, 313–314
noradrenaline, 206, 207t genetics, 316–317
phases of, 192–193, 193–194t neurochemistry, 315–316
serotonin, 206, 207t neurocognitive facets, 312–313
opioids (see Opioids) pharmacological treatment, 317–318
reinforcement principles structural MRI, 315
in animal models, 66–67 heroin intoxication symptoms, 337
drugs of abuse, 67–68, 68f impulsive behavior, 333
emergent withdrawal symptoms, 67–68 maladaptive decision-making process, 333–334
neuroadaptational intersections, 69–70 neural systems (see Neural systems)
positive and negative reinforcement, 64–65 obesity and
secondary and conditioned reinforcement, addictive-like eating, 329–330, 330f
65–66 conceptualization, 335
stress food addiction and substance-use disorders,
and addiction, pathways, 48–49 335–336
and behavioral addictions, 51–53 opiates (see Opiates)
definitions, 44–45 opioids (see Opioids)
genetics and epigenetics, 53–54 PIU and IGD, 318
HPA axis, 46 behavioral treatment, 321–322
integration of, 46–48 DTI, 320
relapse, risk factor, 50–51, 52f electrophysiology, 319
SAM axis, 45 fMRI, 319–320
sex effects, 53 genetics, 321
vulnerability factor, 49–50 neurochemistry, 321
347
348 Index
Addictive disorders (Continued) prevalence of, 296

neurocognitive facets, 318–319 synthetic, 295–296
pharmacological treatment, 322 treatment
structural MRI, 320 bupropion, 301–302
response inhibition (see Response inhibition) cognitive-enhancing medications, 302
sensitization, 331 naltrexone, 303
stress and, 51–53 psychosocial interventions, 301
Alcohol, 148–149 topiramate, 302
A118G OPRM1, human pharmacogenetic studies, Amygdala, 65–66
259–261, 259–260f Anterior cingulate cortex (ACC), 122, 168, 168f
brain function, 230t Apoptotic processes, 21–22, 28–29
decision making and reward processing, 225 Arginine vasopressin (AVP) system, 238–240
inhibitory control, 224 ATS. See Amphetamine-type stimulants (ATS)
verbal encoding, 224–225 Attentional bias (AB), 78, 79f
working memory, 223–224 clinical relevance of, 81–82
brain volume motivation, 78
cerebellum, 219 affective change, 78–79
and cortical thickness findings, 226t affects, 79–80
frontal lobe, 217–219 current concern, 80
hippocampus, 216–217 extensive research, 80–81
insula, 220 incentives, 78–79
subcortical structures, 219–220 noninvasive brain stimulation, 84
clinical studies, naltrexone, 254–255 pharmacological interventions, 83–84
naltrexone clinical trials, pharmacogenetic therapeutic implications, 83
studies, 261–263, 261t Attention deficit/hyperactivity disorder
neuroimaging technology, 215–216 (ADHD), 181
opioids in, 254 Attention training techniques, 129
population study, adolescents, 216 AVP system. See Arginine vasopressin (AVP)
white matter microstructure, 228t system
diffusion tensor imaging, 220
FA, 221
and marijuana, 221–222 B
Alcoholism, 71 b-adrenergic receptors (bARs), 98
Alcohol use disorders (AUDs). See Alcohol Basal ganglia, 219–220
Alzheimer’s disease, 29 Behavioral activation (BA), 129
Amphetamine, 20–21 Behavioral addictions. See also Competing
Amphetamine-type stimulants (ATS) neurobehavioral decision systems (CNDS)
consequences of, 296 theory
illicit drugs, class of, 296 gambling disorder, 312
neurocognitive effects behavioral treatment, 317
brain activation, region-specific alterations, DTI, 315
300 electrophysiology, 313
chronic methamphetamine, 299 fMRI, 313–314
cognition, 299 genetics, 316–317
functional neuroimaging procedures, 300 neurochemistry, 315–316
task indexing reward-related decision-making, neurocognitive facets, 312–313
300–301 pharmacological treatment, 317–318
pharmacology and neurotoxicity structural MRI, 315
dopaminergic system, 298 PIU and IGD, 318
monoamines, 297–298 behavioral treatment, 321–322
neuroanatomy and endogenous opioid DTI, 320
receptors, 298–299 electrophysiology, 319
serotonergic neurons, 297–298 fMRI, 319–320
Index 349
genetics, 321 D
neurochemistry, 321 DAN. See Dorsal attentional network (DAN)
neurocognitive facets, 318–319 D-cycloserine (DCS), 98–99
pharmacological treatment, 322 Death pathways, 21–22
structural MRI, 320 Default mode network (DMN), 122–123
stress and, 51–53 Delay discounting, 271–272
Behavioral traits, 4–5 Diazepam, 24–25
Benzodiazepines, 24–25 Diffusion tensor imaging (DTI), 315, 320
Blood–brain barrier (BBB), 23–24 dlPFC. See Dorsolateral prefrontal
Bupropion, 301–302 cortex (dlPFC)
DMN. See Default mode network (DMN)
Dopamine (DA), 20–21, 28, 64–65, 67–68, 206,
207t, 330–331, 48–49, 315, 5.
C See also Cocaine; Opioids
Calpastatin, 28–29 Dorsal attentional network (DAN), 123
Cannabis, 149–152 Dorsolateral prefrontal cortex (dlPFC), 145,
CBT. See Cognitive behavioral therapy (CBT) 168, 168f
Cerebellum, 219 Drug addiction, 64, 166–168
Cholinergic neurotransmission, 201–202 Drug craving
Chronic stress, drug-induced neurotoxicity, 25 clinical implications
Cocaine, 20–21, 150–151, 244. individualized treatment planning and
See also Dopamine (DA) monitoring, 131
attentional bias for, 81–82 integrated cognitive therapies, 132
dependence, 270–271, 278 multidimensional treatment
Cognitive behavioral therapy (CBT), 317 interventions, 132
Cognitive-enhancing medications, 302 four levels approach, 132–133
Competing neurobehavioral decision systems interventions, 116
(CNDS) theory models of, 117
and cocaine neurocognitive basis
behaviors, 276, 276f attention network, 123, 133f
comorbidities with other substance use and DMN, 123
risky sexual behavior, 277–278 executive control network, 124
differential development, 275 memory networks, 124
hyperactivation of impulsive system, 274–275 region-based perspective, 118, 119t
hypoactivation of executive system, 275 SN, 122
socioeconomic status and addiction, 276–277 striatal-limbic network, 118–122
cocaine treatment neurocognitive interventions
contingency management, 278–279 attention training techniques, 129
conventional treatment, 278 BA strategies, 129
medications, 279–280, 282–283 cognitive-based interventions, 127, 128t
neurocognitive training, 281–282 effortful active suppression, 131
neurotherapeutic stimulation, 280–281, 283 environment engineering, 127
executive decision system, 272 goal setting and motivational enhancement,
in health and addiction, 273, 273f 128–129
impulsive decision system, 272 memory reconsolidation, 130–131
Conditioned reinforcement, 65–66 mindfulness training, 129–130
Corticotropin-releasing factor (CRF), 46 noninvasive transcranial electrical and
Craving, 65–66, 66–67, 93, 94, 173–177, 192–193, magnetic stimulation techniques, 127
274, 280–281, 334, 148, 260, 50–51. pharmacological, 126
See also Drug craving reappraisal training, 130
CRF. See Corticotropin-releasing factor (CRF) neurocognitive model, 125–126, 125f
Cue-reactivity, 4–5 neuroimaging techniques, 116–117
Cyclooxygenase (COX), 29–30 substance use disorder, 116
350 Index
Drug-induced neurotoxicity chronic stress, 25

in addiction medicine diet and nutritional supplies, 26
binge episodes, 31 Excitotoxicity, 22–23
intoxicated patients during overdose, 31 Executive cognitive functions (ECF), 81
nontreatment seekers, 30 Executive control network (ECN), 122, 124
relapse-prone patients, 31 Executive decision system, CNDS theory
severe drug withdrawal symptoms, 31 medications, 282–283
treatment seekers, 30 neurocognitive training
mechanisms and pathways episodic future thinking, 282
apoptotic processes, 21–22 working memory training, 281
biochemical mechanisms, 23 neurotherapeutic stimulation, 283
excitotoxicity, 22–23 Extinction, 99–100
oxidative stress, 20–21
potential preventive strategies F
antiapoptotic approach, 28–29 Feedback-related negativity (FRN), 313
anti-inflammatory approach, 29–30 fMRI. See Functional magnetic resonance imaging
modulating brain dopamine levels, 28 (fMRI)
NMDA receptor antagonism, 29 Food addiction. See Addictive disorders
oxidative challenge, 28 Fractional anisotropy (FA), 221–222
pharmacologic interventions, 27, 27t Frontal lobe, 217–219
rotation in drugs, 29 functional magnetic resonance imaging (fMRI),
thermoregulatory interventions, 30 166, 331
triggering and susceptibility factors
active metabolites and adulterants, 24
age, 26 G
ambient temperature, 25–26 GABA neurotransmission, 204–205
antioxidant status, 26–27 G (aspartate) allele, 255–256
chronic stress, 25 Gambling disorder, 312. See also Internet gaming
diet and nutritional supplies, 26 disorder (IGD)
gender, 26 behavioral treatment, 317
gestational drug exposure, 26 DTI, 315
polydrug abuse, 24–25 electrophysiology, 313
substance withdrawal, 25 fMRI, 313–314
Drug-related factors, neurotoxicity, 24f genetics, 316–317
active metabolites and adulterants, 24 neurochemistry, 315–316
polydrug abuse, 24–25 neurocognitive facets, 312–313
substance withdrawal, 25 pharmacological treatment, 317–318
DSM-5, 116, 312, 336–337 structural MRI, 315
DTI. See Diffusion tensor imaging (DTI) General adaptation syndrome (GAS), 46
Dynorphin systems, 242–243 Glutamate neurotransmission, 203–204
Goal-directed behavior, 100–101, 101f
Goal-directed drug, 104
E
ECF. See Executive cognitive functions (ECF) H
ECN. See Executive control network (ECN) Habenula, 193–200
Ecstasy, 151 Habit formation, 95–97
Electrical stimulation, reinforcing Hippocampus, 124, 216–217
properties of, 66 Histone deacetylase (HDAC) inhibitors, 100
Endocannabinoid signaling, 206 HPA axis. See Hypothalamic-pituitaryadrenal
Endogenous opioid signaling, 205 (HPA) axis
Endogenous opioid systems, 239 Hyperthermia, 23, 30
Environmental factors, drug-induced neurotoxicity Hypothalamic-pituitaryadrenal (HPA) axis, 46,
ambient temperature, 25–26 245–246
Index 351
I extinction, 99–100
IGD. See Internet gaming disorder (IGD) reconsolidation, 98–99
Imbalance, decision systems, 274–275 restoring goal-directed behavior, 100–101, 101f
Impulsive decision system, CNDS theory, 272 in addiction treatment
and cocaine, 274–275 drug memory destabilization mechanisms,
contingency management, 278–279 102–103
medications, 279–280 goal-directed drug, 104
neurotherapeutic stimulation, 280–281 memory specificity and boundary conditions,
Impulsivity, 152–153, 271–272, 333–334 103
Individual-related factors, drug-induced persistence of effects, 103–104
neurotoxicity drug-induced alterations
age, 26 associative learning, 93–94
antioxidant status, 26–27 habit formation, 95–97
gender, 26 translating memory to action, 94–95
gestational drug exposure, 26 Longitudinal prediction, 168, 168f
Inferior frontal gyrus (IFG), 168, 168f Loss of control, 97, 143–144, 329–330
Inhibition
addiction/problematic substance use, M
169–173, 170t Marijuana, 177–178, 221–222
go/no-go studies, 169–172, 170t Melatonin, 28–29
stop-signal tasks, 170t, 172 Memory networks, 124
stroop studies, 170t, 172–173 Memory reconsolidation, 130–131
clinical outcome, prediction of Methamphetamine, 23, 23, 26.
go/no-go studies, 173–177, 174t See also Amphetamine-type stimulants (ATS)
stop-signal studies, 174t, 177 3,4-Methylenedioxy-methamphetamine (MDMA),
stroop studies, 174t, 177–179 20–22, 151
in drug addiction, 167–168, 168f Mindfulness training, 129–130
individual differences, 181 Modafinil, 244–245, 282–283, 302
limitations, and clinical implications, 182–183
neurochemistry, 181–182
paradigm considerations, 180 N
Insula, 122, 220 Naltrexone, 246, 303
Insular cortex, 65–66 in alcoholism, 254–255
Internet addiction, behavioral, 318 pharmacogenetic studies, 260–263, 261t
Internet gaming disorder (IGD), 318. Negative emotionality, 4–5
See also Problematic Internet use (PIU) Negative reinforcement, 64–65
behavioral treatment, 321–322 Neural systems
DTI, 320 addictive disorders
electrophysiology, 319 DSM-5, 336–337
fMRI, 319–320 heroin intoxication symptoms, 337
genetics, 321 emotion dysregulation, 334
neurochemistry, 321 food addiction, 337–339
neurocognitive facets, 318–319 impulsivity
pharmacological treatment, 322 impulsive behavior, 333
structural MRI, 320 maladaptive decision-making process,
Interpeduncular nucleus, 200 333–334
Intoxication, 23, 337 obesity and addiction
Intracranialc self-stimulation (ICSS), 66 addictive-like eating, 329–330, 330f
conceptualization, 335
food addiction and substance-use disorders,
L 335–336
Learning and memory reward dysfunction
in addiction medicine, 92 addictive disorders, 331
352 Index
Neural systems (Continued) maladaptive decision-making process, 333–334

brain regions, reactivity, 331–332 sensitization, 331
chronic cocaine, 332–333 OFC. See Orbitofrontal cortex (OFC)
DA, 330–331 Opiates, 238
D2-like receptor availability, 332 AVP system, 238–240
functional magnetic resonance imaging, 331 endogenous opioid systems, 239
sensitization, 331 dynorphin systems, 242–243
Neuroadaptations, 69 POMC systems, 241–242
Neurocircuitry, 193–201 HPA axis, 245–246
Neuroinflammatory processes, 29–30 orexin and receptors, 243–245
Neuroticism, 4–5 stress-responsive orexin system, 239
Neurotoxicity, 297–299. See also Drug-induced Opioids. See also Alcohol
neurotoxicity A118G OPRM1
Nicotine alcohol, human pharmacogenetic studies,
reinstatement, 192–193 259–261, 259–260f
response inhibition and drugs of abuse, 148 animal model studies, 257–259, 257–258f
withdrawal, 192–193, 194t molecular and cellular effects, 255–256
Nicotine dependence in alcohol, 254
neural substrates naltrexone
cholinergic neurotransmission, 201–202 clinical studies, 261–263, 261t
dopamine, 206, 207t pharmacogenetic studies, 261–263, 261t
endocannabinoid signaling, 206 Orbitofrontal cortex (OFC), 146–147, 179–180, 218
endogenous opioid signaling, 205 Orexin, 239, 243–245
GABA neurotransmission, 204–205 Oxidative stress, 20–21, 28
glutamate neurotransmission, 203–204
noradrenaline, 206, 207t
serotonin, 206, 207t
P
PIU. See Problematic Internet use (PIU)
neurocircuitry, 193–201
Polydrug abuse, 24–25
phases of, 192–193, 193–194t
Positive reinforcement, 64–65
NMDA receptor antagonism, 29
Positron emission tomography (PET), 181–182
N-methyl-D-aspartate (NMDA) glutamate
Prefrontal cortex, 65–66
receptors, 22–23
Pre-supplementary motor area (pre-SMA), 168, 168f
Noradrenaline, 206, 207t
Problematic Internet use (PIU), 318.
Nucleus accumbens, 67–68, 193–200
See also Internet gaming disorder (IGD)
behavioral treatment, 321–322
O DTI, 320
electrophysiology, 319
Obesity
fMRI, 319–320
and addictive disorders
genetics, 321
addictive-like eating, 329–330, 330f
neurochemistry, 321
conceptualization, 335
neurocognitive facets, 318–319
food addiction and substance-use disorders,
pharmacological treatment, 322
335–336
structural MRI, 320
brain regions, reactivity, 331–332
Proopiomelanocortin (POMC) systems, 46, 241–242
chronic cocaine, 332–333
DA, 330–331
D2-like receptor availability, 332 R
DSM-5, 336–337 Reactive oxygen species (ROS), 28
emotion dysregulation, 334 Reappraisal training, 130
food addiction, 337–339 Reconsolidation, 97–99
functional magnetic resonance imaging, 331 Reinforcement principles, addiction medicine
heroin intoxication symptoms, 337 in animal models, 66–67
impulsive behavior, 333 drugs of abuse, 67–68, 68f
Index 353
emergent withdrawal symptoms, 67–68 Sensitization, 244–245, 298–299, 331–332

neuroadaptational intersections, 69–70 Serotonin, 23, 206, 207t
positive and negative reinforcement, 64–65 SSRT. See Stop-signal reaction time (SSRT)
secondary and conditioned reinforcement, 65–66 STN. See Subthalamic nucleus (STN)
Reinstatement, 100, 103, 192–193, 200–202, 205, Stop-signal reaction time (SSRT), 144–145
244–245 Stress
Relapse, 92, 96 and addiction, pathways, 48–49
stress, risk factor, 50–51 and behavioral addictions, 51–53
Repetitive transcranial magnetic stimulation definitions, 44–45
(rTMS), 84 HPA axis, 46
Response inhibition, 166 integration of, 46–48
and abstinence moderators
cannabis, 151–152 genetics and epigenetics, 53–54
cognitive processes, 153 sex effects, 53
impulse control, 152–153 relapse, risk factor, 50–51, 52f
relapse, 151 SAM axis, 45
TMS and tDCS, 153–154 vulnerability factor
abuse drugs animals, developmental studies, 49
alcohol, 148–149 humans, developmental studies, 50
cannabis, 149–150 Striatal-limbic network, 118–122
cocaine, 150–151 Stroop test, 81–82
MDMA/ecstasy, 151 Substance use disorder, 64, 68f, 116
nicotine, 148 Subthalamic nucleus (STN), 145–146
addiction, characteristic of, 143–144 Sympathetic-adrenal-medullary (SAM) axis, 45
cognitive control processes, 144
inhibitory control, 144–145 T
neurobiology, control tDCS. See Transcranial direct current stimulation
dlPFC, 145 (tDCS)
OFC, 146–147 Thalamus, 219–220
rIFC, 145–147 TMS. See Transcranial magnetic stimulation (TMS)
STN, 145–146 Topiramate, 302
STOP task, 145–146, 146f Transcranial direct current stimulation (tDCS), 84
SSRT, 144–145 Transcranial magnetic stimulation (TMS), 145–146,
rIFC. See Right inferior frontal cortex (rIFC) 153–154, 280
Right inferior frontal cortex
(rIFC), 145–147
rTMS. See Repetitive transcranial magnetic V
stimulation (rTMS) V1b systems, 239–240
Ventral striatum, 65–66
S Ventromedial prefrontal cortex (vmPFC), 169
Salience network (SN), 122
SAM axis. See Sympathetic-adrenal-medullary W
(SAM) axis Withdrawal, 25, 67–68, 182, 192–193, 200–201,
Secondary reinforcement, 65–66 336–337
Self-administration, 66 neurotoxicity, 22–23, 25, 31
Self-control failure, CNDS theory, 271 nicotine, 192–193, 194t
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Serial Editor

Mark Bear, Cambridge, USA.

First edition 2016

Copyright # 2016 Elsevier B.V. All rights reserved

For information on all Elsevier publications

There is considerable variability in the likelihood of developing addiction upon

Progress in Brain Research, Volume 223, ISSN 0079-6123, http://dx.doi.org/10.1016/bs.pbr.2015.09.004

For example, polymorphisms affecting the function of the alcohol dehydrogenase

number of common associations of these epigenetic changes, including increased

6 CONCLUSION AND FUTURE DIRECTIONS

High-risk drug use Positive

Progress in Brain Research, Volume 223, ISSN 0079-6123, http://dx.doi.org/10.1016/bs.pbr.2015.07.004

2 DRUG-INDUCED NEUROTOXICITY: MECHANISMS AND

2.1 OXIDATIVE STRESS

amphetamine derivatives, cocaine, 3,4-methylenedioxy-methamphetamine (MDMA),

2.2 APOPTOTIC PROCESSES

evidence supporting the link between excitotoxicity and thiamine deficiency

2.4 INVOLVEMENT OF OTHER BIOCHEMICAL MECHANISMS

3 DRUG-INDUCED NEUROTOXICITY: TRIGGERING AND

3.1 DRUG-RELATED FACTORS

3.1.2 Polydrug abuse

3.1.3 Substance withdrawal

3.2 ENVIRONMENTAL FACTORS

3.2.2 Ambient temperature

3.3 INDIVIDUAL-RELATED FACTORS

3.3.2 The role of gender

3.3.3 Gestational drug exposure

3.3.4 Antioxidant status

4 DRUG-INDUCED NEUROTOXICITY: POTENTIAL PREVENTIVE

Table 1 Potential Pharmacologic Interventions to Prevent Drug-Induced

Modulating dopamine system Dopamine receptor agonists Pramipexole

4.1 MODULATING BRAIN DOPAMINE LEVELS

4.2 ADDRESSING OXIDATIVE CHALLENGE

4.3 ANTIAPOPTOTIC APPROACH

shown to reverse methamphetamine-induced activation of death pathways in dopa-

4.4 NMDA RECEPTOR ANTAGONISM

4.5 ROTATION IN DRUGS

4.6 ANTI-INFLAMMATORY APPROACH

to undergo damage during the early stages of methamphetamine-induced neurotox-

4.7 THERMOREGULATORY INTERVENTIONS

5 DRUG-INDUCED NEUROTOXICITY IN ADDICTION MEDICINE

5.1 TREATMENT SEEKERS

5.2 NONTREATMENT SEEKERS

5.3 RELAPSE-PRONE PATIENTS

5.4 INTOXICATED PATIENTS DURING OVERDOSE OR BINGE EPISODES

5.5 CLIENTS SUFFERING FROM SEVERE DRUG WITHDRAWAL

6 CONCLUSION AND FUTURE DIRECTIONS

45 (4), 484–492. Available at: http://www.sciencedirect.com/science/article/pii/

expect there to be a convergence of evidence from an analysis of such domains as

2 STRESS RESPONSE SYSTEMS

2.1 SYMPATHETIC-ADRENAL-MEDULLARY AXIS

2.2 HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

2.3 THE INTEGRATION OF THE STRESS RESPONSE

(N-arachidonylethanolamine anandamide) and 2-AG (2-arachidonoylglycerol).

2.4 COMMON PATHWAYS BETWEEN STRESS AND ADDICTION

3 STRESS AS A VULNERABILITY FACTOR FOR INITIATION

3.2 DEVELOPMENTAL STUDIES IN HUMANS

4 STRESS AS A RISK FACTOR FOR RELAPSE

distress-induced relapse is a powerful negative reinforcement for persistent smoking

5 STRESS AND BEHAVIORAL ADDICTIONS

sympathetic, serotonergic, dopaminergic, and endogenous opioid systems, has been

hypersexuality, internet use disorder, and noneating disordered excessive eating

6 MODERATORS OF THE STRESS EFFECTS ON THE