Geoff Varty

Overactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been linked to affective disorders such as anxiety and depression. Dampening HPA activity has, therefore, been considered as a possible means of treating affective disorders. Given the important role of vasopressin in modulating the HPA axis, one strategy has focused on inhibiting activity of the vasopressin 1b (V1b) receptor. In animals, V1b receptor antagonists reduce plasma stress hormone levels and have been shown to have an… Show more

Overactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been linked to affective disorders such as anxiety and depression. Dampening HPA activity has, therefore, been considered as a possible means of treating affective disorders. Given the important role of vasopressin in modulating the HPA axis, one strategy has focused on inhibiting activity of the vasopressin 1b (V1b) receptor. In animals, V1b receptor antagonists reduce plasma stress hormone levels and have been shown to have an anxiolytic-like effect. Recently, V1B-30N was identified as a highly potent V1b receptor antagonist with selectivity over other vasopressin receptors, which is evaluated here in rodent models of anxiety-like and depression-like behaviors. V1B-30N (1-30mg/kg, IP) dose-dependently reduced separation-induced vocalizations in rat pups without producing any sedative effects in the animals. Similarly, V1B-30N (3-30mg/kg, IP) dose-dependently reduced separation-induced vocalizations in guinea pig pups. In a conflict assay, conditioned lick suppression, V1B-30N (3-30mg/kg, IP) increased punished licking. To assess antidepressive-like properties, V1B-30N (1-30mg/kg) was tested in the mouse and rat forced-swim tests but was found to be inactive. These results are consistent with previous findings with other V1b antagonists, which suggest that acute pharmacological antagonism of the V1b receptor has anxiolytic-like but not antidepressant-like properties. Show less

SAR110894 is a novel histamine H₃-R ligand, displaying high and selective affinity for human, rat or mouse H₃-Rs. SAR110894 is a potent H₃-R antagonist at native receptors, reversing R-α-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPγS binding at human H₃-Rs demonstrating inverse agonist properties. In behavioral models addressing certain aspects of cognitive impairment associated with… Show more

SAR110894 is a novel histamine H₃-R ligand, displaying high and selective affinity for human, rat or mouse H₃-Rs. SAR110894 is a potent H₃-R antagonist at native receptors, reversing R-α-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPγS binding at human H₃-Rs demonstrating inverse agonist properties. In behavioral models addressing certain aspects of cognitive impairment associated with schizophrenia (CIAS) and attention deficit/hyperactivity disorder (ADHD), SAR110894 improved memory performances in several variants of the object recognition task in mice (0.3-3 mg/kg, p.o.) or rats (0.3-1 mg/kg, p.o.). Moreover, SAR110894 (1 mg/kg, p.o.) reversed a deficit in working memory in the Y-maze test, following an acute low dose of phencyclidine (PCP) (0.5 mg/kg, i.p.) in mice sensitized by repeated treatment with a high dose of PCP (10 mg/kg, i.p.). In the latent inhibition (LI) model, SAR110894 potentiated LI in saline-treated rats (1 and 3 mg/kg, i.p.) and reversed abnormally persistent LI induced by neonatal nitric oxide synthase (NOS) inhibition in rodents (0.3-3 mg/kg, i.p.). In a social novelty discrimination task in rats, SAR110894 attenuated selective attention deficit induced by neonatal PCP treatment (3 and 10 mg/kg, p.o.) or a parametric modification of the procedure (3 and 10 mg/kg, p.o.). SAR110894 showed efficacy in several animal models related to the cognitive deficits in Alzheimer's disease (AD). It prevented the occurrence of episodic memory deficit induced by scopolamine in rats (0.01-10 mg/kg, p.o.) or by the central infusion of the toxic amyloid fragment β₂₅₋₃₅ in the object recognition test in mice (1 and 3 mg/kg, p.o.). Altogether, these findings suggest that SAR110894 may be of therapeutic interest for the treatment of the cognitive symptoms of AD, schizophrenia and certain aspects of ADHD. Show less

NK1 receptor antagonists have been shown to have a variety of physiological and potential therapeutic effects in animal models and in humans. The present studies demonstrate that Rolapitant (SCH 619734, (5S)-8(S)-[[1(R)-[3,5 bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4,5]decan-2-one) is a selective, bioavailable, CNS penetrant neurokinin NK1 receptor antagonist that shows behavioral effects in animals models of emesis. In vitro studies indicate that rolapitant has a high… Show more

NK1 receptor antagonists have been shown to have a variety of physiological and potential therapeutic effects in animal models and in humans. The present studies demonstrate that Rolapitant (SCH 619734, (5S)-8(S)-[[1(R)-[3,5 bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4,5]decan-2-one) is a selective, bioavailable, CNS penetrant neurokinin NK1 receptor antagonist that shows behavioral effects in animals models of emesis. In vitro studies indicate that rolapitant has a high affinity for the human NK1 receptor of 0.66 nM and high selectivity over the human NK2 and NK3 subtypes of >1000-fold, as well as preferential affinity for human, guinea pig, gerbil and monkey NK1 receptors over rat, mouse and rabbit. Rolapitant is a functionally competitive antagonist, as measured by calcium efflux, with a calculated Kb of 0.17 nM. Rolapitant reversed NK1 agonist-induced foot tapping in gerbils following both intravenous and oral administration up to 24 hours at a minimal effective dose (MED) of 0.1 mg/kg. Rolapitant was active at 0.1 and 1 mg/kg in both acute and delayed emesis models in ferrets, respectively, consistent with clinical data for other NK1 antagonists. Clinical efficacy of anti-emetics is highly correlated with efficacy in the ferret emesis model, suggesting rolapitant is a viable clinical candidate for this indication. Show less

The endogenous opioid-like peptide, nociceptin, produces anxiolytic-like effects that are mediated via the nociceptin (NOP) receptor. Similarly, synthetic, non-peptide NOP agonists produce robust anxiolytic-like effects although these effects are limited by marked side effects. In the present studies, the effects of a novel NOP receptor agonist, SCH 655842, were examined in rodent models sensitive to anxiolytic drugs and tests measuring potential adverse affects. Oral administration of SCH… Show more

The endogenous opioid-like peptide, nociceptin, produces anxiolytic-like effects that are mediated via the nociceptin (NOP) receptor. Similarly, synthetic, non-peptide NOP agonists produce robust anxiolytic-like effects although these effects are limited by marked side effects. In the present studies, the effects of a novel NOP receptor agonist, SCH 655842, were examined in rodent models sensitive to anxiolytic drugs and tests measuring potential adverse affects. Oral administration of SCH 655842 produced robust, anxiolytic-like effects in three species, i.e., rat, guinea pig, and mouse. Specifically, SCH 655842 was effective in rat conditioned lick suppression (3-10 mg/kg) and fear-potentiated startle (3-10 mg/kg) tests, a guinea pig pup vocalization test (1-3 mg/kg), as well as in mouse Geller-Seifter (30 mg/kg) and marble burying (30 mg/kg) tests. The anxiolytic-like effect of SCH 655842 in the conditioned lick suppression test was attenuated by the NOP antagonist, J-113397. In mice, SCH 655842 reduced locomotor activity and body temperature at doses similar to the anxiolytic-like dose and these effects were absent in NOP receptor knockout mice. In rats, SCH 655842 did not produce adverse behavioral effects up to doses of 70-100 mg/kg. Pharmacokinetic studies in the rat confirmed dose-related increases in plasma and brain levels of SCH 655842 across a wide oral dose range. Taken together, SCH 655842 may represent a NOP receptor agonist with improved tolerability compared to other members of this class although further studies are necessary to establish whether this extends to higher species. Show less

RATIONALE:
The psychotomimetic effects of cannabis are believed to be mediated via cannabinoid CB1 receptors. Furthermore, studies have implicated CB1 receptors in the pathophysiology of schizophrenia.
OBJECTIVE:
These studies investigated the effects of the CB1 receptor antagonist, AVE1625, in acute pharmacological and neurodevelopmental models of schizophrenia. AVE1625 was administered to rodents alone or as a co-treatment with clinically used antipsychotic drugs… Show more

RATIONALE:
The psychotomimetic effects of cannabis are believed to be mediated via cannabinoid CB1 receptors. Furthermore, studies have implicated CB1 receptors in the pathophysiology of schizophrenia.
OBJECTIVE:
These studies investigated the effects of the CB1 receptor antagonist, AVE1625, in acute pharmacological and neurodevelopmental models of schizophrenia. AVE1625 was administered to rodents alone or as a co-treatment with clinically used antipsychotic drugs (APDs).
METHODS:
The antipsychotic potential of AVE1625 was tested using psychotomimetic-induced hyperactivity and latent inhibition (LI) deficit models. The procognitive profile was assessed using hole board, novel object recognition, auditory evoked potential, and LI techniques. In addition, the side-effect profile was established by measuring catalepsy, antipsychotic-induced weight gain, plasma levels of prolactin, and anxiogenic potential.
RESULTS:
AVE1625 (1, 3, and 10 mg/kg ip), reversed abnormally persistent LI induced by MK-801 or neonatal nitric oxide synthase inhibition in rodents, and improved both working and episodic memory. AVE1625 was not active in positive symptom models but importantly, it did not diminish the efficacy of APDs. It also decreased catalepsy and weight gain induced by APDs, suggesting that it may decrease APD-induced extrapyramidal side effects (EPS) and compliance. Unlike other CB1 antagonists, AVE1625 did not produce anxiogenic-like effects.
CONCLUSIONS:
These preclinical data suggest that AVE1625 may be useful to treat the cognitive deficits in schizophrenia and as a co-treatment with currently available antipsychotics. In addition, an improved side-effect profile was seen, with potential to ameliorate the EPS and weight gain issues with currently available treatments. Show less

The current work extends our previous findings in stress-related disorders, but also addresses the impact of a neurokinin-2 (NK2) antagonist on cognition. Besides efficacy in mood disorders, an NK2 antagonist may have the potential to lack the disinhibitory components and adverse side effects associated with existing clinical treatments. Saredutant (3-30 mg/kg, per os, p.o.) was tested for anxiolytic-like potential in three mouse models: holeboard, stress-induced hyperthermia (SIH) and… Show more

The current work extends our previous findings in stress-related disorders, but also addresses the impact of a neurokinin-2 (NK2) antagonist on cognition. Besides efficacy in mood disorders, an NK2 antagonist may have the potential to lack the disinhibitory components and adverse side effects associated with existing clinical treatments. Saredutant (3-30 mg/kg, per os, p.o.) was tested for anxiolytic-like potential in three mouse models: holeboard, stress-induced hyperthermia (SIH) and four-plate. In the holeboard model saredutant (30 mg/kg) showed a trend to increase head dipping without affecting general activity. In the SIH model, saredutant demonstrated a significant reduction in stress-induced temperature at 30 mg/kg, while the number of punished crossings in the four-plate was increased at all doses tested (3-30 mg/kg). While chlordiazepoxide (CDP) demonstrated anxiolytic-like effects in these models, the adverse side effects of benzodiazepines, such as sedation, disinhibition and cognitive deficits are well-documented. Saredutant produced no detrimental effect in three models of cognition: Morris Water Maze (MWM) in rats, spontaneous alternation in a Y-maze in mice and novel objection recognition in mice. In contrast, the benzodiazepine, diazepam (DZM), produced cognitive impairments. NK2 receptor antagonists like saredutant may therefore yield beneficial effects for mood disorders without the adverse effects of current treatments. Show less

We define the pharmacological and pharmacokinetic profiles of a novel α(2C)-adrenoceptor agonist, compound A [N-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1,4-benzoxazin-6-yl]-N-ethyl-N'-methylurea]. This compound has high affinity (K(i)) for the human α(2C)-adrenoceptor (K(i) = 12 nM), and 190- to 260-fold selectivity over the α(2A)- and α(2B)-adrenoceptor subtypes. In cell-based functional assays, compound A produced good agonist (EC(50) = 166 nM) and efficacy (E(max) = 64%) responses at the… Show more

We define the pharmacological and pharmacokinetic profiles of a novel α(2C)-adrenoceptor agonist, compound A [N-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1,4-benzoxazin-6-yl]-N-ethyl-N'-methylurea]. This compound has high affinity (K(i)) for the human α(2C)-adrenoceptor (K(i) = 12 nM), and 190- to 260-fold selectivity over the α(2A)- and α(2B)-adrenoceptor subtypes. In cell-based functional assays, compound A produced good agonist (EC(50) = 166 nM) and efficacy (E(max) = 64%) responses at the α(2C)-adrenoceptor, much lower potency and efficacy at the α(2A)-adrenoceptor (EC(50) = 1525 nM; E(max) = 8%) and α(2B)-adrenoceptor (EC(50) = 5814 nM; E(max) = 21%) subtypes, and low or no affinity and functional activity at the α(1A)-, α(1B)-, and α(1D)-adrenoceptor subtypes. In the human saphenous vein postjunctional α(2C)-adrenoceptor bioassay, compound A functions as a potent agonist (pD(2) = 6.3). In a real-time contraction bioassay of pig nasal mucosa, compound A preferentially constricted the veins (EC(50) = 108 nM), and the magnitude of arteriolar contraction reached only 50% of the maximum venular responses. Compound A exhibited no effect on locomotor activity, sedation, and body temperature in mice (up to 100 mg/kg) and did not cause hypertension and mydriasis (30 mg/kg) in conscious rats. Compound A is orally bioavailable (24%) with good plasma exposure. This compound is a substrate for the efflux P-glycoprotein transporter, resulting in very low central nervous system (CNS) penetration. In summary, compound A is a highly selective, orally active, and non-CNS-penetrating α(2C)-adrenoceptor agonist with desirable in vitro and in vivo pharmacological properties suitable for the treatment of nasal congestion. Show less

Antagonism of the adenosine A(2A) receptor affords a possible treatment of Parkinson's disease. In the course of investigating pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A(2A) antagonists, we prepared [1,2,4]-triazolo[4,3-c]pyrimidin-3-ones with potent and selective (vs A(1)) A(2A) antagonist activity. Structure-activity relationships are described for this series.

Modification of prototype NK(1) antagonist 2 resulted in the synthesis of a series of simple amides 6 and retroamides 9. These compounds were shown to be potent and orally active NK(1) antagonists.

Parkinson's Disease (PD) and Extrapyramidal Syndrome (EPS) are movement disorders that result from degeneration of the dopaminergic input to the striatum and chronic inhibition of striatal dopamine D(2) receptors by antipsychotics, respectively. Adenosine A(2A) receptors are selectively localized in the basal ganglia, primarily in the striatopallidal ("indirect") pathway, where they appear to operate in concert with D(2) receptors and have been suggested to drive striatopallidal output balance.… Show more

Parkinson's Disease (PD) and Extrapyramidal Syndrome (EPS) are movement disorders that result from degeneration of the dopaminergic input to the striatum and chronic inhibition of striatal dopamine D(2) receptors by antipsychotics, respectively. Adenosine A(2A) receptors are selectively localized in the basal ganglia, primarily in the striatopallidal ("indirect") pathway, where they appear to operate in concert with D(2) receptors and have been suggested to drive striatopallidal output balance. In cases of dopaminergic hypofunction, A(2A) receptor activation contributes to the overdrive of the indirect pathway. A(2A) receptor antagonists, therefore, have the potential to restore this inhibitor imbalance. Consequently, A(2A) receptor antagonists have therapeutic potential in diseases of dopaminergic hypofunction such as PD and EPS. Targeting the A(2A) receptor may also be a way to avoid the issues associated with direct dopamine agonists. Recently, preladenant was identified as a potent and highly selective A(2A) receptor antagonist, and has produced a significant improvement in motor function in rodent models of PD. Here we investigate the effects of preladenant in two primate movement disorder models. In MPTP-treated cynomolgus monkeys, preladenant (1 or 3 mg/kg; PO) improved motor ability and did not evoke any dopaminergic-mediated dyskinetic or motor complications. In Cebus apella monkeys with a history of chronic haloperidol treatment, preladenant (0.3-3.0 mg/kg; PO) delayed the onset of EPS symptoms evoked by an acute haloperidol challenge. Collectively, these data support the use of preladenant for the treatment of PD and antipsychotic-induced movement disorders. Show less

We describe the pharmacological and pharmacokinetic profiles of SCH 486757, a nociceptin/orphanin FQ peptide (NOP) receptor agonist that has recently entered human clinical trials for cough. SCH 486757 selectively binds human NOP receptor (K(i)=4.6+/-0.61nM) over classical opioid receptors. In a guinea pig capsaicin cough model, SCH 486757 (0.01-1mg/kg) suppressed cough at 2, 4, and 6h post oral administration with a maximum efficacy occurring at 4h equivalent to codeine, hydrocodone… Show more

We describe the pharmacological and pharmacokinetic profiles of SCH 486757, a nociceptin/orphanin FQ peptide (NOP) receptor agonist that has recently entered human clinical trials for cough. SCH 486757 selectively binds human NOP receptor (K(i)=4.6+/-0.61nM) over classical opioid receptors. In a guinea pig capsaicin cough model, SCH 486757 (0.01-1mg/kg) suppressed cough at 2, 4, and 6h post oral administration with a maximum efficacy occurring at 4h equivalent to codeine, hydrocodone, dextromethorphan and baclofen. The antitussive effects of SCH 486757 (3.0mg/kg, p.o.) was blocked by the NOP receptor antagonist J113397 (12mg/kg, i.p.) but not by naltrexone (10mg/kg, p.o.). SCH 486757 does not produce tolerance to its antitussive activity after a 5-day BID dosing regimen. After acute and chronic dosing paradigms, SCH 486757 (1mg/kg) inhibited capsaicin-evoked coughing by 46+/-9% and 40+/-11%, respectively. In a feline mechanically-evoked cough model, SCH 486757 produces a maximum inhibition of cough and expiratory abdominal electromyogram amplitude of 59 and 61%, respectively. SCH 486757 did not significantly affect inspiratory electromyogram amplitude. We examined the abuse potential of SCH 486757 (10mg/kg, p.o.) in a rat conditioned place preference procedure which is sensitive to classical drugs of abuse, such as amphetamine and morphine. SCH 486757 was without effect in this model. Finally, SCH 486757 displays a good oral pharmacokinetic profile in the guinea pig, rat and dog. We conclude that SCH 486757 has a favorable antitussive profile in preclinical animal models. Show less

Vasopressin 1b (V1b) antagonists have been postulated as possible treatments for depression and anxiety. A novel series of potent and selective V1b antagonists has been identified starting from an in-house screen hit. The incorporation of a sulfonamide linker between a tetrahydroisoquinoline core and amino piperidine lead to the identification of a V1b antagonist with similar affinity for human and rat receptors. Further optimization of the right hand portion afforded potent V1b antagonists… Show more

Vasopressin 1b (V1b) antagonists have been postulated as possible treatments for depression and anxiety. A novel series of potent and selective V1b antagonists has been identified starting from an in-house screen hit. The incorporation of a sulfonamide linker between a tetrahydroisoquinoline core and amino piperidine lead to the identification of a V1b antagonist with similar affinity for human and rat receptors. Further optimization of the right hand portion afforded potent V1b antagonists that possessed moderate to high selectivity over other receptors. Show less

The adenosine A(2A) receptor has been implicated in the underlying biology of various neurological and psychiatric disorders, including Parkinson's disease (PD) and depression. Preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] are potent competitive antagonists of the human A(2A) receptor (K(i) = 1.1 and 0.6 nM, respectively) and have >1000-fold selectivity over all other adenosine receptors… Show more

The adenosine A(2A) receptor has been implicated in the underlying biology of various neurological and psychiatric disorders, including Parkinson's disease (PD) and depression. Preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] are potent competitive antagonists of the human A(2A) receptor (K(i) = 1.1 and 0.6 nM, respectively) and have >1000-fold selectivity over all other adenosine receptors, making these compounds the most selective A(2A) receptor antagonists reported to date. Both compounds attenuate hypolocomotion induced by the A(2A) receptor agonist CGS-21680 [2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine], suggesting that they inhibit A(2A) receptor activity in vivo. Their high degree of selectivity and robust in vivo activity make preladenant and SCH 412348 useful tools to investigate the role of the A(2A) receptor system in animal models of PD and depression. Oral administration of preladenant and SCH 412348 (0.1-1 mg/kg) to rats potentiated 3,4-dihydroxy-L-phenylalanine (L-Dopa)-induced contralateral rotations after 6-hydroxydopamine lesions in the medial forebrain bundle and potently attenuated the cataleptic effects of haloperidol. Preladenant (1 mg/kg) inhibited L-Dopa-induced behavioral sensitization after repeated daily administration, which suggests a reduced risk of the development of dyskinesias. Finally, preladenant and SCH 412348 exhibited antidepressant-like profiles in models of behavioral despair, namely the mouse tail suspension test and the mouse and rat forced swim test. These studies demonstrate that preladenant and SCH 412348 are potent and selective A(2A) receptor antagonists and provide further evidence of the potential therapeutic benefits of A(2A) receptor inhibition in PD (with reduced risk of dyskinesias) and depression (one of the primary nonmotor symptoms of PD). Show less

The discovery of 1 as a high-affinity ligand for the nociceptin receptor has led to the synthesis of a series of tropane (8-methyl-8-azabicyclo[3.2.1]octane) derivatives as optimized ligands. These compounds exhibit high affinity for the nociceptin receptor, moderate to excellent selectivity over the opioid mu receptor, and behave as full agonists. In this Letter, we present the synthesis and highlight the structure-activity relationship of tropane derivatives culminating in the identification… Show more

The discovery of 1 as a high-affinity ligand for the nociceptin receptor has led to the synthesis of a series of tropane (8-methyl-8-azabicyclo[3.2.1]octane) derivatives as optimized ligands. These compounds exhibit high affinity for the nociceptin receptor, moderate to excellent selectivity over the opioid mu receptor, and behave as full agonists. In this Letter, we present the synthesis and highlight the structure-activity relationship of tropane derivatives culminating in the identification of 24 and 32 as potent and orally active antitussive and anxiolytic agents. The in vitro and in vivo activities, pharmacokinetic profile, and the hPXR activity, which predicts the potential 3A4 induction in human, are disclosed. Show less

RATIONALE:
Vasopressin (AVP) plays a role in regulating anxiety, which is thought to be partially mediated through the V1a receptor. Recently, JNJ-17308616 was identified as a V1a antagonist.
OBJECTIVES:
The purpose of this work was to assess V1a receptor affinity and selectivity of JNJ-17308616 and in vivo efficacy in animal models of anxiety-like behavior.
MATERIALS AND METHODS:
The affinity of JNJ-17308616 for the human and rat V1a, V1b, V2, and oxytocin receptors was… Show more

RATIONALE:
Vasopressin (AVP) plays a role in regulating anxiety, which is thought to be partially mediated through the V1a receptor. Recently, JNJ-17308616 was identified as a V1a antagonist.
OBJECTIVES:
The purpose of this work was to assess V1a receptor affinity and selectivity of JNJ-17308616 and in vivo efficacy in animal models of anxiety-like behavior.
MATERIALS AND METHODS:
The affinity of JNJ-17308616 for the human and rat V1a, V1b, V2, and oxytocin receptors was determined. Central administration of AVP induces a scratching response mediated through the V1a receptor. Inhibition of scratching was used as a behavioral measure of in vivo potency. JNJ-17308616 was tested in five models of anxiety: rat elevated plus-maze (EPM), rat-elevated zero-maze (EZM), rat-conditioned lick suppression (CLS), rat pup separation-induced ultrasonic vocalizations (USV), and mouse marble burying (MMB).
RESULTS:
High affinity for the human V1a receptor (K (i) 5.0 nM) was confirmed. However, the rat V1a receptor affinity was more modest (K (i) 216 nM), and the compound was not selective over the rat V2 receptor (K (i) 276 nM). At 100 mg/kg, JNJ-17308616 significantly reduced anxiety-like behavior in EPM, USV, and MMB; at 30 mg/kg, it was effective in EZM and CLS. JNJ-17308616 neither impaired social recognition nor reduced locomotor activity.
CONCLUSIONS:
These results demonstrate the potential for V1a receptor antagonists as novel anxiolytics. Tool compounds that have greater V1a receptor selectivity than JNJ-17308616 are necessary to make precise conclusions about the role of the V1a receptor in affective disorders. Show less

RATIONALE:
Adenosine and dopamine interact within the striatum to control striatopallidal output and globus pallidus GABA release. Manipulating striatal adenosine transmission via blockade of the A2A receptor subtype can compensate for the reduced dopamine activity within the striatum that underlies movement disorders such as antipsychotic-induced extrapyramidal syndrome (EPS) and Parkinson's disease (PD). Preclinical studies in the rat have demonstrated that adenosine A2A receptor… Show more

RATIONALE:
Adenosine and dopamine interact within the striatum to control striatopallidal output and globus pallidus GABA release. Manipulating striatal adenosine transmission via blockade of the A2A receptor subtype can compensate for the reduced dopamine activity within the striatum that underlies movement disorders such as antipsychotic-induced extrapyramidal syndrome (EPS) and Parkinson's disease (PD). Preclinical studies in the rat have demonstrated that adenosine A2A receptor antagonists can attenuate behaviors reflecting reduced dopamine activity, such as haloperidol-induced catalepsy and hypoactivity.
OBJECTIVES:
In the present studies using nonhuman primates, adenosine antagonists were tested against haloperidol-induced EPS in Cebus apella and haloperidol-induced catalepsy in Saimiri sciureus (squirrel monkey). Specifically, the A2A receptor antagonists, SCH 412348 (0.3-30 mg/kg PO) and KW-6002 (3-100 mg/kg PO); the A1/A2A receptor antagonist, caffeine (1-30 mg/kg PO and IM); and the A1 receptor antagonist, DPCPX (3-30 mg/kg PO) were tested in at least one of these models.
RESULTS:
SCH 412348 (10-30 mg/kg), KW-6002 (57-100 mg/kg), and caffeine (30 mg/kg) significantly increased the time to EPS onset. Additionally, SCH 412348, KW-6002, and caffeine afforded protection from the onset of EPS for at least 6 h in some of the primates. SCH 412348 (10 mg/kg) and caffeine (10 mg/kg) significantly reduced haloperidol-induced catalepsy. DPCPX produced a very slight attenuation of EPS at 30 mg/kg, but had no effect on catalepsy.
CONCLUSIONS:
These findings suggest that adenosine A2A receptor antagonists may represent an effective treatment for the motor impairments associated with both antipsychotic-induced EPS and PD. Show less

Vasopressin and corticotropin releasing factor (CRF) are both critical regulators of an animal's stress response and have been linked to anxiety and depression. As such, antagonists of the CRF1 and V1b receptor subtypes are being developed as potential treatments for affective disorders. The two most characterized V1b and CRF1 antagonists are SSR149415 and CP-154,526, respectively, and the present studies were designed to compare these two compounds in acute animal models of affective… Show more

Vasopressin and corticotropin releasing factor (CRF) are both critical regulators of an animal's stress response and have been linked to anxiety and depression. As such, antagonists of the CRF1 and V1b receptor subtypes are being developed as potential treatments for affective disorders. The two most characterized V1b and CRF1 antagonists are SSR149415 and CP-154,526, respectively, and the present studies were designed to compare these two compounds in acute animal models of affective disorders. We employed five anxiety models: Separation-induced pup vocalizations (guinea pig and rat), elevated plus-maze (EPM), conditioned lick suppression (CLS), and marble burying (mouse); as well as three depression models: forced swim test (FST; mouse and rat) and tail suspension test (TST; mouse). SSR149415 (1-30 mg/kg) was active in the vocalization, EPM and CLS models, but inactive in marble burying. CP-154,526 (1-30 mg/kg) was active in vocalization models, but inactive in EPM, CLS, and marble burying. SSR149415 was inactive in all depression models; CP-154,526 was active in rat FST but inactive in mouse models. This work demonstrates the different profiles of V1b and CRF1 receptor antagonists and supports both approaches in the treatment of affective disorders. Show less

Prepulse inhibition can be reliably disrupted by non-competitive NMDA receptor antagonists such as dizocilpine. In recent study, we found that the potent D2/5-HT2 receptor antagonist, risperidone, but not the selective dopamine D2 receptor antagonist, raclopride, could reverse this disruption. The present study was therefore designed to examine the effect of the 5-HT2 receptor antagonist, ketanserin, against a dizocilpine-induced disruption of prepulse inhibition, as well as the behavioural… Show more

Prepulse inhibition can be reliably disrupted by non-competitive NMDA receptor antagonists such as dizocilpine. In recent study, we found that the potent D2/5-HT2 receptor antagonist, risperidone, but not the selective dopamine D2 receptor antagonist, raclopride, could reverse this disruption. The present study was therefore designed to examine the effect of the 5-HT2 receptor antagonist, ketanserin, against a dizocilpine-induced disruption of prepulse inhibition, as well as the behavioural stereotypy produced by this drug. Ketanserin (2 mg/kg) reversed the prepulse inhibition disruption produced by dizocilpine (0.15 mg/kg), as did the non-selective 5-HT1/5-HT2 receptor antagonist metergoline (1 mg/kg). Both drugs also attenuated some components of the behavioural stereotypy syndrome produced by dizocilpine (0.15 mg/kg). The present studies therefore suggest an interaction between 5-HT2 receptors and glutamatergic systems. This may be important for the antipsychotic profile of drugs having antagonist activity at 5-HT2 receptors. Show less

RATIONALE:
Previous studies have demonstrated behaviors indicative of anxiolysis in rats pretreated with the nociceptin receptor (opioid receptor like-1, ORL-1) agonist, Ro64-6198.
OBJECTIVES:
The aim of this study was to examine the effects of Ro64-6198 in anxiety models across three species: rat, guinea pig, and mouse. In addition, the receptor specificity of Ro64-6198 was studied, using the ORL-1 receptor antagonist, J-113397, and ORL-1 receptor knockout (KO) mice. Finally… Show more

RATIONALE:
Previous studies have demonstrated behaviors indicative of anxiolysis in rats pretreated with the nociceptin receptor (opioid receptor like-1, ORL-1) agonist, Ro64-6198.
OBJECTIVES:
The aim of this study was to examine the effects of Ro64-6198 in anxiety models across three species: rat, guinea pig, and mouse. In addition, the receptor specificity of Ro64-6198 was studied, using the ORL-1 receptor antagonist, J-113397, and ORL-1 receptor knockout (KO) mice. Finally, neurological studies examined potential side effects of Ro64-6198 in the rat and mouse.
RESULTS:
Ro64-6198 (3-10 mg/kg) increased punished responding in a rat conditioned lick suppression test similarly to chlordiazepoxide (6 mg/kg). This effect of Ro64-6198 was attenuated by J-113397 (10 mg/kg), but not the mu opioid antagonist, naltrexone (3 mg/kg). In addition, Ro64-6198 (1-3 mg/kg) reduced isolation-induced vocalizations in rat and guinea pig pups. Ro64-6198 (3 mg/kg) increased the proportion of punished responding in a mouse Geller-Seifter test in wild-type (WT) but not ORL-1 KO mice, whereas diazepam (1-5.6 mg/kg) was effective in both genotypes. In rats, Ro64-6198 reduced locomotor activity (LMA) and body temperature and impaired rotarod, beam walking, and fixed-ratio (FR) performance at doses of 10-30 mg/kg, i.e., three to ten times higher than an anxiolytic dose. In WT mice, Ro64-6198 (3-10 mg/kg) reduced LMA and rotarod performance, body temperature, and FR responding, but these same measures were unaffected in ORL-1 KO mice. Haloperidol (0.3-3 mg/kg) reduced these measures to a similar extent in both genotypes. These studies confirm the potent, ORL-1 receptor-mediated, anxiolytic-like effects of Ro64-6198, extending the findings across three species. Ro64-6198 has target-based side effects, although the magnitude of these effects varies across species.
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A series of novel five- and six-membered ring urea derivatives have been described as potent and selective NK1 receptor antagonists. Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compounds are also described herein.

The structure-activity relationship (SAR) exploration using 2-(2-furanyl)-7-phenyl[1,2,4]triazolo-[1,5-c]pyrimidin-5-amine (1) as a template led to the identification of a novel class of potent and selective adenosine A2A receptor (AR) antagonists. However, these compounds were found to be associated with significant hERG activity. This report discusses the strategy and outcome of an expanded SAR focused on addressing the hERG liability. As a result, compounds 21 and 24 possess excellent in… Show more

The structure-activity relationship (SAR) exploration using 2-(2-furanyl)-7-phenyl[1,2,4]triazolo-[1,5-c]pyrimidin-5-amine (1) as a template led to the identification of a novel class of potent and selective adenosine A2A receptor (AR) antagonists. However, these compounds were found to be associated with significant hERG activity. This report discusses the strategy and outcome of an expanded SAR focused on addressing the hERG liability. As a result, compounds 21 and 24 possess excellent in vitro profiles, highly promising in vivo profiles, and acceptable levels of hERG channel inhibition. Show less

The structure-activity relationship of this novel class of compounds based on 2-(2-furanyl)-7-phenyl[1,2,4]-triazolo[1,5-c]pyrimidin-5-amine, 1, and its analogs was evaluated for their in vitro and in vivo adenosine A(2A) receptor antagonism. Several compounds displayed oral activity at 3 mg/kg in a rat catalepsy model. Specifically, compound 8g displayed an excellent in vitro profile, as well as a highly promising in vivo profile.

RATIONALE:
Modulation of metabotropic glutamate receptor (mGluR) subtypes represents a novel approach for the treatment of neurological and psychiatric disorders.
OBJECTIVES:
This study was conducted to investigate the role of the mGluR5 and mGluR1 subtypes in the modulation of pain and anxiety.
METHODS:
The mGluR5 antagonists, 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), and the mGluR1 antagonist… Show more

RATIONALE:
Modulation of metabotropic glutamate receptor (mGluR) subtypes represents a novel approach for the treatment of neurological and psychiatric disorders.
OBJECTIVES:
This study was conducted to investigate the role of the mGluR5 and mGluR1 subtypes in the modulation of pain and anxiety.
METHODS:
The mGluR5 antagonists, 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), and the mGluR1 antagonist, (4-methoxy-phenyl)-(6-methoxy-quinazolin-4-yl)-amine HCl (LY456236), were tested in models of pain [mouse formalin test, rat spinal nerve ligation (SNL)] and anxiety [Vogel conflict, conditioned lick suppression (CLS)], and their efficacious effects were compared to any associated side effects.
RESULTS:
The systemic administration of MPEP, MTEP, and LY456236 reduced hyperalgesia induced by formalin and mechanical allodynia following SNL. However, only LY456236 completely reversed the allodynia. In the anxiety models, MPEP (3--30 mg/kg), MTEP (3--10 mg/kg), and LY456236 (10--30 mg/kg) produced anxiolytic-like effects similar to the benzodiazepine, chlordiazepoxide (CDP, 6 mg/kg). However, only MPEP and MTEP were able to produce a level of anxiolysis comparable to CDP. In a series of tests examining potential side effects, MPEP and MTEP reduced body temperature and locomotor activity and impaired operant responding for food and rotarod performance at doses of 3--30 and 1--30 mg/kg, respectively. LY456236 reduced operant responding at 30 mg/kg.
CONCLUSION:
Both mGluR5 and mGluR1 antagonists are effective in models of pain and anxiety. However, an mGluR1 antagonist was more efficacious than the two mGluR5 antagonists in the pain models, which, conversely, appeared more efficacious in the anxiety models. These findings support the potential utility of mGluR5 and mGluR1 antagonists for both the treatment of chronic pain and as novel anxiolytics. Show less

Prior work has demonstrated that melanin-concentrating hormone-1 (MCH-1) receptor antagonism decreases food intake and body weight in obese rodents. The purpose of this study was to determine if the MCH-1 receptor antagonist-mediated hypophagia was due a decrease in meal size, meal frequency, or both. We performed a meal pattern analysis in free-feeding hyperphagic diet-induced obese (DIO) rats treated with 1, 3 or 10 mg/kg p.o. of the MCH-1 receptor antagonist T-226296 (a (-)enantiomer of… Show more

Prior work has demonstrated that melanin-concentrating hormone-1 (MCH-1) receptor antagonism decreases food intake and body weight in obese rodents. The purpose of this study was to determine if the MCH-1 receptor antagonist-mediated hypophagia was due a decrease in meal size, meal frequency, or both. We performed a meal pattern analysis in free-feeding hyperphagic diet-induced obese (DIO) rats treated with 1, 3 or 10 mg/kg p.o. of the MCH-1 receptor antagonist T-226296 (a (-)enantiomer of N-[6-(dimethylamino)-methyl]-5,6,7,8-tetrahydro-2-naphthalenyl]-4'-fluoro[1,1'-biphenyl]-4 carboxamide). Food intake was continuously monitored for 24 h using a BioDAQ food intake monitoring system. A total of 10 mg/kg T-226296 significantly decreased body weight and 24-h food intake, and had no effect on locomotor activity. The decrease in food intake was due to a reduction in meal size, not meal frequency. We conclude that MCH-1 receptor antagonism with T-226296 decreases food intake in DIO rats by selectively reducing meal size, and that the reduced food intake is not due to a generalized behavioral malaise. Show less

The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic methyl compound 3 led to the methoxymethyl analogue 30, which had excellent receptor selectivity and oral bioavailability in rats and monkeys. Compound 30 (Sch-417690/Sch-D), a potent inhibitor of HIV-1 entry into target cells, is currently in clinical trials.

Prepulse inhibition (PPI), a form of sensorimotor gating, occurs when an auditory startle response is markedly inhibited by a preceding sub-threshold stimulus (prepulse). Deficits in PPI have been demonstrated in patients with certain psychiatric disorders, such as schizophrenia, and in laboratory animals following specific pharmacological manipulations. Patients with Alzheimer's disease (AD) have not been tested in PPI, but have been shown to have abnormal sensory gating in another paradigm… Show more

Prepulse inhibition (PPI), a form of sensorimotor gating, occurs when an auditory startle response is markedly inhibited by a preceding sub-threshold stimulus (prepulse). Deficits in PPI have been demonstrated in patients with certain psychiatric disorders, such as schizophrenia, and in laboratory animals following specific pharmacological manipulations. Patients with Alzheimer's disease (AD) have not been tested in PPI, but have been shown to have abnormal sensory gating in another paradigm. Transgenic (Tg) CRND8 mice, which model Alzheimer's disease, carry the Swedish and Indiana familial Alzheimer's disease mutations of the human amyloid precursor protein gene and show age-related increases in beta-amyloid (Abeta) production, as well as plaque deposition. The present experiment investigated auditory startle threshold and PPI in TgCRND8 mice at various ages. In two longitudinal studies, PPI was examined in male TgCRND8 mice and non-transgenic (non-Tg) controls at 6-8 weeks of age (pre-plaque), and every 2 weeks thereafter until all mice were at least 16 weeks old (post-plaque). In a cross-sectional study, three different age sets of nai;ve TgCRND8 and non-Tg mice were tested: 10-12, 12-14, and 15-17 weeks old. In all three studies, TgCRND8 mice consistently and robustly demonstrated an enhanced response to a range of auditory startle stimuli compared to non-Tg mice. In addition, the TgCRND8 mice exhibited modest reductions in PPI, compared to non-Tg controls. These PPI deficits were present at pre- and post-plaque time points and did not appear to intensify with age; thus, they do not seem to correlate with the known neuropathology of TgCRND8 mice. Show less

Hemokinin-1 (HK-1) is a recently described mouse tachykinin peptide whose biological functions are not fully understood. To date, a unique receptor for HK-1 has not been identified. Recent studies suggest HK-1 may have a role in immunological functions, but there has been little characterization of HK-1's effects in the central nervous system (CNS). In the present studies, we confirm that HK-1 is an endogenous agonist at all of the known tachykinin receptors, and is selective for the NK1… Show more

Hemokinin-1 (HK-1) is a recently described mouse tachykinin peptide whose biological functions are not fully understood. To date, a unique receptor for HK-1 has not been identified. Recent studies suggest HK-1 may have a role in immunological functions, but there has been little characterization of HK-1's effects in the central nervous system (CNS). In the present studies, we confirm that HK-1 is an endogenous agonist at all of the known tachykinin receptors, and is selective for the NK1 receptor over the NK2 and NK3 subtypes. CHO cells transfected with the human NK1 receptor released intracellular calcium in response to HK-1. In addition, HK-1 competed with substance P (SP) for binding to mouse NK1 and human NK1 receptors. In vivo central administration of HK-1 to gerbils and mice induced foot-tapping and scratching behaviors, respectively, similar to those observed following central administration of SP or the NK1 receptor agonist, GR-73632. Furthermore, these behavioral effects were blocked by the selective NK1 receptor antagonist, MK-869. Finally, a comprehensive expression analysis of HK-1 demonstrated that HK-1 mRNA is much more broadly expressed than previously reported with expression observed in many brain regions. Together these data demonstrate that HK-1 is a functional agonist at NK1 receptors and suggest that HK-1 may function both centrally and peripherally. Show less

Recent clinical evidence supports the potential of neurokinin NK1 receptor antagonists as novel antidepressant drugs. A number of NK1 antagonists have reduced affinity for rat and mouse NK1 receptors compared to human, making it difficult to test for efficacy in traditional animal models. NK1 antagonists, in general, have similar affinity at gerbil and human NK1 receptors. The aims of these studies were first, to validate the gerbil tail suspension test, a test used frequently to demonstrate… Show more

Recent clinical evidence supports the potential of neurokinin NK1 receptor antagonists as novel antidepressant drugs. A number of NK1 antagonists have reduced affinity for rat and mouse NK1 receptors compared to human, making it difficult to test for efficacy in traditional animal models. NK1 antagonists, in general, have similar affinity at gerbil and human NK1 receptors. The aims of these studies were first, to validate the gerbil tail suspension test, a test used frequently to demonstrate antidepressant drug efficacy in mice, and second, to determine whether the test could be used to demonstrate the antidepressant potential of NK1 antagonists. Immobility time was reduced by oral administration of the antidepressants imipramine (3-30 mg/kg), desipramine (1-30 mg/kg), amitriptyline (30 mg/kg), fluoxetine (1-30 mg/kg), paroxetine (3-10 mg/kg), citalopram (0.1-3 mg/kg), sertraline (1-30 mg/kg), venlafaxine (1-30 mg/kg) and nefazodone (100 mg/kg). Furthermore, oral administration of the NK1 antagonists MK-869 (10 mg/kg), L-742694 (10 mg/kg), L-733060 (10 mg/kg), CP-99994 (30 mg/kg), and CP-122721 (3-30 mg/kg) reduced immobility time. Diazepam (1-10 mg/kg), chlordiazepoxide (1-10 mg/kg), buspirone (3-30 mg/kg), FG-7142 (1-30 mg/kg), and haloperidol (1-10 mg/kg) did not reduce immobility. Amphetamine (0.3-10 mg/kg) and atropine (0.3-10 mg/kg) reduced immobility, suggesting susceptibility to false positives, e.g. compounds that affect locomotion. Compounds were therefore tested in a gerbil locomotor activity (LMA) test to ensure that the antidepressant-like effects were not secondary to effects on activity. Antidepressant drugs and NK1 antagonists had no effect on LMA at doses that reduced immobility, whereas amphetamine and atropine induced marked hyperactivity. These studies support both the utility of gerbils in behavioral pharmacology and the antidepressant potential of selective NK1 antagonists. Show less

Several neurokinin NK1 receptor antagonists currently being developed for anxiety and depression have reduced affinity for the rat and mouse NK1 receptor compared with human. Consequently, it has proven difficult to test these agents in traditional rat and mouse models of anxiety and depression. This issue has been overcome, in part, by using non-traditional lab species such as the guinea pig and gerbil, which have NK1 receptors closer in homology to human NK1 receptors. However, there are very… Show more

Several neurokinin NK1 receptor antagonists currently being developed for anxiety and depression have reduced affinity for the rat and mouse NK1 receptor compared with human. Consequently, it has proven difficult to test these agents in traditional rat and mouse models of anxiety and depression. This issue has been overcome, in part, by using non-traditional lab species such as the guinea pig and gerbil, which have NK1 receptors closer in homology to human NK1 receptors. However, there are very few reports describing the behavior of gerbils in traditional models of anxiety. The aim of the present study was to determine if the elevated plus-maze, a commonly used anxiety model, could be adapted for the gerbil. Using a specially-designed elevated plus-maze, gerbils exhibited an 'anxious' behavioral profile similar to that observed in rats and mice, i.e., reduced entries into, and time spent exploring, an open, aversive arm. The anxiolytic drugs diazepam (0.03-3 mg/kg i.p.), chlordiazepoxide (0.3-10 mg/kg i.p.), and buspirone (0.3-30 mg/kg s.c.) increased open arm exploration and produced anxiolytic-like effects on risk-assessment behaviors (reduced stretch-attend postures and increased head dips). Of particular interest, the antidepressant drugs imipramine (1-30 mg/kg p.o.), fluoxetine (1-30 mg/kg, p.o.) and paroxetine (0.3-10 mg/kg p.o.) each produced some acute anxiolytic-like activity, without affecting locomotor activity. The antipsychotic, haloperidol, and the psychostimulant, amphetamine, did not produce any anxiolytic-like effects (1-10 mg/kg s.c). The anxiogenic beta-carboline, FG-7142, reduced time spent in the open arm and head dips, and increased stretch-attend postures (1-30 mg/kg, i.p.). These studies have demonstrated that gerbils exhibit an anxiety-like profile on an elevated plus-maze, and that the gerbil elevated plus-maze may have predictive validity for anxiolytics, and antidepressants with potential anxiolytic-like effects. Show less

Neurokinin NK1 receptor antagonists may have therapeutic potential in the treatment of anxiety and depression. Species variants in the NK1 receptor result in reduced affinity of NK1 receptor antagonists at rat and mouse NK1 receptors, making it difficult to test NK1 antagonists in traditional preclinical models of anxiety and depression. Gerbil NK1 receptors are similar in homology to the human NK1 receptor. In a companion article, we described the anxiety-like behavioral profile of gerbils on… Show more

Neurokinin NK1 receptor antagonists may have therapeutic potential in the treatment of anxiety and depression. Species variants in the NK1 receptor result in reduced affinity of NK1 receptor antagonists at rat and mouse NK1 receptors, making it difficult to test NK1 antagonists in traditional preclinical models of anxiety and depression. Gerbil NK1 receptors are similar in homology to the human NK1 receptor. In a companion article, we described the anxiety-like behavioral profile of gerbils on an adapted elevated plus-maze, and the ability of anxiolytic drugs to produce anti-anxiety effects in the gerbil elevated plus-maze. The aim of the present study was to determine whether oral (p.o.) administration of the NK1 receptor antagonists MK-869, L-742,694, L-733,060, CP-99,994, and CP-122,721 produced anxiolytic-like effects in the gerbil elevated plus-maze. Upon testing, all five NK1 antagonists produced anxiolytic-like effects. MK-869 (0.01-3 mg/kg) was the most potent NK1 antagonist, producing anxiolytic-like effects on percentage of open arm time, percentage of open arm entries, stretch-attend postures, and head dips at 0.03-0.3 mg/kg doses. L-742,694 (1-30 mg/kg) and L-733,060 (1-10 mg/kg) produced anxiolytic-like effects on percentage of open arm time and stretch-attend postures at 3-10 mg/kg doses. CP-99,994 (3-30 mg/kg) only produced an anxiolytic-like effect on stretch-attend postures. CP-122,721 (3-30 mg/kg) produced an anxiolytic-like effect on percentage of open arm time at 30 mg/kg. The order of potency of the NK1 antagonists to increase percentage of open arm time was very similar to their potency to block NK1 agonist-induced foot-tapping. These studies demonstrate that neurokinin NK1 receptor antagonists produce anxiolytic-like effects in a novel gerbil elevated plus-maze, and suggest that this is an appropriate model to test NK1 antagonists for preclinical anxiolytic activity. Show less

Interest in central neurokinin (NK) 1 receptors has increased based on reports of the therapeutic potential for NK1 antagonists in anxiety and depression. In these studies, an ex vivo binding procedure was used to correlate NK1 receptor occupancy in striatum by NK1 antagonists with their potency to inhibit NK1 agonist-induced foot tapping in gerbils (GFT). The following compounds were administered orally: CP-99,994, L-742,694, MK-869, CP-122,721, L-760,735-F, GR205171, L-733,060, and L-733,061.… Show more

Interest in central neurokinin (NK) 1 receptors has increased based on reports of the therapeutic potential for NK1 antagonists in anxiety and depression. In these studies, an ex vivo binding procedure was used to correlate NK1 receptor occupancy in striatum by NK1 antagonists with their potency to inhibit NK1 agonist-induced foot tapping in gerbils (GFT). The following compounds were administered orally: CP-99,994, L-742,694, MK-869, CP-122,721, L-760,735-F, GR205171, L-733,060, and L-733,061. Two hours later, gerbils received the NK1 agonist GR73632 [H(2)N-(CH(2))(4)-CO-Phe-Pro-NMe-Leu-Met-NH(2)] i.c.v. and foot tapping was measured for 5 min. The same procedure was used for ex vivo binding studies except that saline, rather than agonist, was administered i.c.v. before dissection of the striatum. The tissue homogenate was then used in an equilibrium radioligand binding assay. When IC(50) values for inhibition of ex vivo (125)I-substance P binding by NK1 antagonists were compared with the corresponding EC(50) values for inhibition of GFT, a significant positive correlation was observed (r(2) = 0.97, p < 0.001). This result indicates that increased NK1 receptor occupancy in striatum by NK1 antagonists parallels the inhibition of agonist-mediated GFT. For all compounds, the dose that produced the maximum inhibition of GFT resulted in less than 100% ex vivo receptor occupancy in striatum. When gerbils did not receive the i.c.v. saline injection before ex vivo binding, thereby leaving the blood-brain barrier (BBB) intact, the IC(50) values for antagonists were unchanged, suggesting that potential damage to the BBB caused by the i.c.v. injection did not affect determinations of antagonist potency in the GFT model. Show less

The dopamine agonist apomorphine robustly disrupts prepulse inhibition of the acoustic startle response in the rat, yet published studies have not demonstrated a robust disruption of prepulse inhibition with apomorphine in the mouse. The aim of these studies was to establish the optimal prepulse conditions (using manipulations to prepulse intensity and inter-stimulus interval) and mouse strain(s) for testing apomorphine, and also the prepulse inhibition disrupting drugs amphetamine, and… Show more

The dopamine agonist apomorphine robustly disrupts prepulse inhibition of the acoustic startle response in the rat, yet published studies have not demonstrated a robust disruption of prepulse inhibition with apomorphine in the mouse. The aim of these studies was to establish the optimal prepulse conditions (using manipulations to prepulse intensity and inter-stimulus interval) and mouse strain(s) for testing apomorphine, and also the prepulse inhibition disrupting drugs amphetamine, and dizocilpine (MK-801). The effects of these drugs on startle response and prepulse inhibition were tested in outbred CD-1 and Swiss Webster (CFW) strains, and the inbred C57BL/6, 129X1/SvJ, and A/J strains. There were strain differences with baseline startle and prepulse inhibition in that the CD-1, CFW, and C57BL/6 strains exhibited high levels of startle and prepulse inhibition, the 129X1/SvJ strain exhibited low levels of startle but high levels of prepulse inhibition, while the A/J strain exhibited low startle and no prepulse inhibition. Apomorphine disrupted prepulse inhibition in the CFW and C57BL/6 strains and the effect was only evident when using a short 30 ms inter-stimulus interval. Amphetamine disrupted prepulse inhibition in the CFW, C57BL/6, and 129X1/SvJ strains, and dizocilpine disrupted prepulse inhibition in the CD-1, CFW, C57BL/6, and 129X1/SvJ strains. The effects of amphetamine and dizocilpine were independent of the inter-stimulus interval. These studies demonstrated clear strain differences in the startle response and prepulse inhibition, and the pharmacological disruptions of prepulse inhibition, and suggest that inter-stimulus intervals less than 100 ms may be optimal for detecting the effects of apomorphine in mice. Show less

BACKGROUND:
Laboratory rats exhibit behavioral changes that reflect a continuum of early life experience, from isolation-reared to socially reared to enrichment-reared conditions. In this study, we further characterize the behavioral effects of isolation, social, and enriched rearing on locomotor activity, patterns of movement and exploration, startle reactivity, prepulse inhibition (PPI), and habituation in adult rats.
METHODS:
Male Sprague-Dawley rat pups (21 days old) were housed… Show more

BACKGROUND:
Laboratory rats exhibit behavioral changes that reflect a continuum of early life experience, from isolation-reared to socially reared to enrichment-reared conditions. In this study, we further characterize the behavioral effects of isolation, social, and enriched rearing on locomotor activity, patterns of movement and exploration, startle reactivity, prepulse inhibition (PPI), and habituation in adult rats.
METHODS:
Male Sprague-Dawley rat pups (21 days old) were housed under enrichment (three per cage with toys and exposure to enriched environments), normal social (three per cage), or isolation (one per cage) conditions. Eight weeks later, locomotor and exploratory behaviors, acoustic startle reactivity, PPI, and habituation were measured in the three groups.
RESULTS:
Enrichment-reared rats exhibited reduced exploration and rapid habituation of locomotor activity, increased startle reactivity, and normal PPI and startle habituation compared with socially reared controls. Isolation-reared rats exhibited increased exploration and normal habituation of locomotor activity, increased startle reactivity, reduced PPI, and normal startle habituation.
CONCLUSIONS:
Isolation- and enrichment-reared rats exhibited opposite changes in some behaviors and similar changes in other behaviors. Specifically, rats raised in enriched conditions appear more efficient at assimilating stimuli from their environment than do rats reared in isolation. Nevertheless, both enrichment- and isolation-rearing conditions increased startle reactivity, whereas only isolation rearing led to disruptions of PPI in adulthood. These results suggest that isolation- and enrichment-rearing conditions produce some common and some differential effects on how rats process environmental stimuli. For studies of isolation-rearing effects on PPI, however, the complex and resource-intensive enrichment condition seems to offer few advantages over the normal social condition. Show less

We examined the discriminative stimulus effects of the high-efficacy dopamine D(1) receptor agonist (+/-)6-chloro-7, 8-dihydroxy-3-ally1-phenyl-2,3,4,5-tetrahydro-1H-3benzazepine++ + hydrobromide (SKF-82958) in rats trained to discriminate SKF-82958 (0.03 mg/kg) from vehicle in a two-lever food-reinforced drug discrimination task. SKF-82958 produced dose-related increases in responding to the SKF-82958 appropriate lever with full substitution occurring at the training dose. Pretreatment with… Show more

We examined the discriminative stimulus effects of the high-efficacy dopamine D(1) receptor agonist (+/-)6-chloro-7, 8-dihydroxy-3-ally1-phenyl-2,3,4,5-tetrahydro-1H-3benzazepine++ + hydrobromide (SKF-82958) in rats trained to discriminate SKF-82958 (0.03 mg/kg) from vehicle in a two-lever food-reinforced drug discrimination task. SKF-82958 produced dose-related increases in responding to the SKF-82958 appropriate lever with full substitution occurring at the training dose. Pretreatment with the dopamine D(1)/D(5) receptor antagonist (-)-trans-6,7,7a,8,9, 13b-hexahydro-3-chloro-2hydroxy-N-methyl-5H-benzo-[d]naphtho -¿2, 1-b¿azepine (SCH-39166) (0.01 mg/kg) attenuated the discriminative stimulus effects of SKF-82958. Pretreatment with the dopamine D(2) receptor antagonist raclopride (0.03 mg/kg) had no effect. The high-efficacy dopamine D(1) receptor agonist R(+)6chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-81297) fully substituted for SKF-82958, whereas the low-efficacy dopamine D(1) receptor agonist (+/-)1-phenyl-2,3,4, 5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393) produced only partial substitution. The dopamine D(2) receptor agonist trans-(+/-)-4,4a,5,6,7,8,8a, 9-octahydro-5-propyl-1H-propyl-1H-pyrazolo[3,4-g]quinoline dihydrochloride (quinpirole) and the indirect dopamine agonist cocaine did not substitute fully for the SKF-82958 discriminative stimulus cue. These results demonstrate that the high-efficacy dopamine D(1) receptor agonist SKF-82958 can serve as an effective discriminative stimulus in the rat, and that these effects are mediated by a dopamine D(1)-like receptor mechanism. Show less

Rats housed in social isolation postweaning (isolates) show profound behavioral and neurobiological differences when compared to socially housed rats (socials). Fischer rats (F344) relative to Lewis rats are hyperresponsive and significantly more susceptible to stressful stimuli. This investigation tested the hypothesis that the behavioral effects of postweaning isolation are more pronounced in a strain of rats with high susceptibility to stress compared to a strain with low susceptibility to… Show more

Rats housed in social isolation postweaning (isolates) show profound behavioral and neurobiological differences when compared to socially housed rats (socials). Fischer rats (F344) relative to Lewis rats are hyperresponsive and significantly more susceptible to stressful stimuli. This investigation tested the hypothesis that the behavioral effects of postweaning isolation are more pronounced in a strain of rats with high susceptibility to stress compared to a strain with low susceptibility to stress. Seventy male Sprague-Dawley, Lewis, and F344 rats were housed individually or in groups at weaning on Day 21 and tested on Day 85 in the Behavioral Pattern Monitor. There was no interaction between strain and postweaning isolation for measures of locomotor activity and exploratory behavior (holepoking). However, the postweaning isolation-induced increase in the frequency of repetitive straight movements, a measure of behavioral organization, was more pronounced in Lewis isolates compared to Sprague-Dawley and F344 isolates. These results do not support the hypothesis that rats with a higher susceptibility to stress show more pronounced changes in behavior following postweaning isolation; instead, increased susceptibility to stress may counteract the repetitive movement patterns induced by social isolation. Show less

Brain dopamine (DA) systems are involved in the modulation of the sensorimotor gating phenomenon known as prepulse inhibition (PPI). The class of D2-like receptors, including the D2, D3, and D4 receptor subtypes, have all been implicated in the control of PPI via studies of DA agonists and antagonists in rats. Nevertheless, the functional relevance of each receptor subtype remains unclear because these ligands are not specific. To determine the relevance of each receptor subtype, we used… Show more

Brain dopamine (DA) systems are involved in the modulation of the sensorimotor gating phenomenon known as prepulse inhibition (PPI). The class of D2-like receptors, including the D2, D3, and D4 receptor subtypes, have all been implicated in the control of PPI via studies of DA agonists and antagonists in rats. Nevertheless, the functional relevance of each receptor subtype remains unclear because these ligands are not specific. To determine the relevance of each receptor subtype, we used genetically altered strains of "knock-out" mice lacking the DA D2, D3, or D4 receptors. We tested the effects of each knock-out on both the phenotypic expression of PPI and the disruption of PPI produced by the indirect DA agonist d-amphetamine (AMPH). No phenotypic differences in PPI were observed at baseline. AMPH significantly disrupted PPI in the D2 (+/+) mice but had no effect in the D2 (-/-) mice. After AMPH treatment, both DA D3 and D4 receptor (+/+) and (-/-) mice had significant disruptions in PPI. These findings indicate that the AMPH-induced disruption of PPI is mediated via the DA D2 receptor and not the D3 or D4 receptor subtypes. Uncovering the neural mechanisms involved in PPI will further our understanding of the substrates of sensorimotor gating and could lead to better therapeutics to treat gating disorders, such as schizophrenia. Show less

In a previous study, rats reared in isolation from weaning exhibited normal prepulse inhibition (PPI) before puberty, whilst after puberty (6-8 weeks post weaning) isolation reared rats exhibited deficits in PPI. The developmental timing of the onset of this isolation effect appears to be critical because similar isolation of adult rats has no effect on PPI. The present study examined the time and duration of the period or 'window' of isolation necessary to induce these behavioral changes. Male… Show more

In a previous study, rats reared in isolation from weaning exhibited normal prepulse inhibition (PPI) before puberty, whilst after puberty (6-8 weeks post weaning) isolation reared rats exhibited deficits in PPI. The developmental timing of the onset of this isolation effect appears to be critical because similar isolation of adult rats has no effect on PPI. The present study examined the time and duration of the period or 'window' of isolation necessary to induce these behavioral changes. Male Sprague-Dawley rats were isolated for either only the first 2 weeks from weaning, only the first 4 weeks from weaning, only weeks 3 and 4, or continuously from weaning (ISO group), and compared with rats reared in normal social conditions (SOC group). Eight weeks after weaning, we compared acoustic and airpuff startle reactivity, acoustic and light PPI, and acoustic and airpuff startle habituation across the groups. There were no significant changes in any of the measures in the groups exposed to 2- or 4-week periods of isolation. In the ISO and SOC groups, acoustic or airpuff startle reactivity was similar, while acoustic PPI was reduced significantly in the ISO group. Airpuff startle habituation was increased significantly in the ISO group compared to SOC controls and there was a similar trend with acoustic startle habituation. These results indicate that only animals isolated for more than 4 weeks after weaning display deficits in PPI, and provide evidence that there is no critical pre-pubertal developmental window for inducing PPI deficits, rather, continuous post-weaning isolation is needed to induce the PPI deficit effect. Show less

In a recent study using Wistar rats, the serotonergic 5-HT2 receptor antagonists ketanserin and risperidone reduced the disruptive effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine on prepulse inhibition (PPI), suggesting that there is an interaction between serotonin and glutamate in the modulation of PPI. In contrast, studies using the noncompetitive NMDA antagonist phencyclidine (PCP) in Sprague-Dawley rats found no effect with 5-HT2 antagonists. To test the… Show more

In a recent study using Wistar rats, the serotonergic 5-HT2 receptor antagonists ketanserin and risperidone reduced the disruptive effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine on prepulse inhibition (PPI), suggesting that there is an interaction between serotonin and glutamate in the modulation of PPI. In contrast, studies using the noncompetitive NMDA antagonist phencyclidine (PCP) in Sprague-Dawley rats found no effect with 5-HT2 antagonists. To test the hypothesis that strain differences might explain the discrepancy in these findings, risperidone was tested for its ability to reduce the PPI-disruptive effects of dizocilpine in Wistar and Sprague-Dawley rats. Furthermore, to determine which serotonergic receptor subtype may mediate this effect, the 5-HT2A receptor antagonist M100907 (formerly MDL 100,907) and the 5-HT2C receptor antagonist SDZ SER 082 were tested against dizocilpine. Recent studies have found that the PPI-disruptive effects of PCP are reduced by the alpha 1 adrenergic receptor antagonist prazosin. Furthermore, the alpha 1 receptor agonist cirazoline disrupts PPI. As risperidone and M100907 have affinity at the alpha 1 receptor, a final study examined whether M100907 would block the effects of cirazoline on PPI. Risperidone partially, but nonsignificantly, reduced the effects of dizocilpine in Wistar rats, although this effect was smaller than previously reported. Consistent with previous studies, risperidone did not alter the effects of dizocilpine in Sprague-Dawley rats. Most importantly, M100907 pretreatment fully blocked the effect of dizocilpine in both strains; whereas SDZ SER 082 had no effect. M100907 had no influence on PPI by itself and did not reduce the effects of cirazoline on PPI. These studies confirm the suggestion that serotonin and glutamate interact in modulating PPI and indicate that the 5-HT2A receptor subtype mediates this interaction. Show less

Isolation rearing of rat pups from weaning produces neurochemical and behavioural changes that may have relevance to the neurodevelopmental basis of neuropsychiatric disorders such as schizophrenia. Although limited, studies have begun to probe for neuroanatomical changes produced by isolation rearing. In the present study, rat pups were reared in isolation, i.e., housed one per cage, from weaning. After 8 weeks of isolation, 'isolates' were compared to their socially reared controls (housed… Show more

Isolation rearing of rat pups from weaning produces neurochemical and behavioural changes that may have relevance to the neurodevelopmental basis of neuropsychiatric disorders such as schizophrenia. Although limited, studies have begun to probe for neuroanatomical changes produced by isolation rearing. In the present study, rat pups were reared in isolation, i.e., housed one per cage, from weaning. After 8 weeks of isolation, 'isolates' were compared to their socially reared controls (housed three per cage) in two behavioural paradigms: locomotor activity in a novel open field and prepulse inhibition (PPI) of the acoustic startle response. Subsequently, all rats were sacrificed and their brains removed. The hippocampus was sectioned and analysed immunohistochemically using an antibody to the synapse-specific protein synaptophysin, to gain an estimate of the synaptic content of selected hippocampal subfields. Isolates demonstrated locomotor hyperactivity and deficits in PPI relative to socially reared controls. Analysis of synaptophysin immunoreactivity suggested that isolates had significantly reduced synaptic content in the hippocampal dentate gyrus molecular layer, with smaller, non-significant reductions in the CA1 and CA3 regions. This pattern of change may be consistent with reduced neuronal input to the dentate gyrus via the entorhinal cortex, suggesting developmental changes in hippocampal-cortical circuitry. These preliminary studies extend the characterisation of isolation rearing as a model for the investigation of neurodevelopmental diseases such as schizophrenia. Show less

This study compared the interaction of strain with isolation rearing on startle reactivity, habituation, and prepulse inhibition (PPI) in male Lewis, Sprague-Dawley, and Fischer F344 rats tested as adults. Lewis and Fischer rats exhibited lower startle reactivity than Sprague-Dawley rats. Lewis rats displayed more rapid habituation than the other strains. Most important, isolation rearing produced deficits in PPI in both Sprague-Dawley and Fischer rats but had no effect in Lewis rats. By… Show more

This study compared the interaction of strain with isolation rearing on startle reactivity, habituation, and prepulse inhibition (PPI) in male Lewis, Sprague-Dawley, and Fischer F344 rats tested as adults. Lewis and Fischer rats exhibited lower startle reactivity than Sprague-Dawley rats. Lewis rats displayed more rapid habituation than the other strains. Most important, isolation rearing produced deficits in PPI in both Sprague-Dawley and Fischer rats but had no effect in Lewis rats. By contrast, isolation rearing had no effect on startle reactivity or habituation. In a separate study, 0.5 mg/kg apomorphine disrupted PPI in Fischer but not in Lewis rats. Thus, PPI in Lewis rats is relatively unaffected by either a pharmacological or a developmental manipulation, both of which disrupt PPI in Sprague-Dawley and Fischer F344 rats. Show less

The dopamine D3/D2 receptor agonists 7-OH-DPAT, quinpirole, quinelorane, and PD128907, the mixed dopamine agonist apomorphine, the D2 agonist bromocriptine, and the D1/D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition (PPI) in Wistar rats. As dopamine agonist-induced hypothermia has been proposed as a model of D3 receptor function, and dopamine agonists are known to disrupt PPI, drug potencies to induce hypothermia were established and compared with doses… Show more

The dopamine D3/D2 receptor agonists 7-OH-DPAT, quinpirole, quinelorane, and PD128907, the mixed dopamine agonist apomorphine, the D2 agonist bromocriptine, and the D1/D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition (PPI) in Wistar rats. As dopamine agonist-induced hypothermia has been proposed as a model of D3 receptor function, and dopamine agonists are known to disrupt PPI, drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI. 7-OH-DPAT, quinpirole, quinelorane, PD128907, and apomorphine, reduced body temperature and disrupted PPI with a similar rank order of potency (quinelorane > quinpirole = 7-OH-DPAT > PD128907 = apomorphine). Bromocriptine and SKF38393 were ineffective in both models. In a separate study, the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI. In a final set of studies, the D2/D3 antagonist raclopride blocked both 7-OH-DPAT-induced hypothermia and 7-OH-DPAT-induced PPI disruption. The 5-HT1A antagonist WAY 100,135, and the peripheral D2-like antagonist domperidone had no effect. These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors; however, only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors. Show less

The effects of aging on acoustic and airpuff startle reactivity, acoustic and airpuff startle habituation, acoustic and cross-modal (light-acoustic) prepulse inhibition (PPI), and fear-potentiated startle (FPS) were examined using 3- (Y: young), 11- (AD: adult), 17- (MA: middle-aged), and 22- (O: old) month-old Fischer F344 rats. AD rats had the highest acoustic startle reactivity with the Y and MA rats showing smaller and comparable startle levels. The O rats had diminished startle reactivity,… Show more

The effects of aging on acoustic and airpuff startle reactivity, acoustic and airpuff startle habituation, acoustic and cross-modal (light-acoustic) prepulse inhibition (PPI), and fear-potentiated startle (FPS) were examined using 3- (Y: young), 11- (AD: adult), 17- (MA: middle-aged), and 22- (O: old) month-old Fischer F344 rats. AD rats had the highest acoustic startle reactivity with the Y and MA rats showing smaller and comparable startle levels. The O rats had diminished startle reactivity, with over a 65% reduction in responding. Airpuff startle reactivity was comparable in the Y and AD groups, while the MA and O groups had 40% and 80% reductions in airpuff startle respectively. There was an age-related increase in airpuff startle habituation. Acoustic and cross-modal PPI were reduced significantly in O rats when compared to other age groups. Finally, there were no effects of age on FPS. In summary, these studies suggest that in Fischer F344 rats, there are age-associated differences in startle reactivity, startle habituation, and PPI, but no aging effect on FPS. Show less

Studies examined methodological differences that might account for discrepant reports related to the ability of clozapine to restore prepulse inhibition (PPI) of acoustic startle in apomorphine (APO)-treated rats. Changes in PPI after APO and clozapine were compared in Sprague. Dawley (SD) versus Wistar rats. In SD rats, intraperitoneal administration of clozapine (4-12 mg/kg) completely reversed the PPI-disruptive effects of APO (0.5 mg/kg), with significant effects evident at the lowest dose… Show more

Studies examined methodological differences that might account for discrepant reports related to the ability of clozapine to restore prepulse inhibition (PPI) of acoustic startle in apomorphine (APO)-treated rats. Changes in PPI after APO and clozapine were compared in Sprague. Dawley (SD) versus Wistar rats. In SD rats, intraperitoneal administration of clozapine (4-12 mg/kg) completely reversed the PPI-disruptive effects of APO (0.5 mg/kg), with significant effects evident at the lowest dose of clozapine. Compared to SD rats, Wistars exhibited a relatively weaker (but statistically significant) disruption of PPI with the same or higher doses of APO and were also less sensitive to the PPI-restorative effects of clozapine. Clozapine administered via subcutaneous route completely restored PPI after APO treatment in SD rats. Discrepant findings with this model can be attributed to differences in rat strain; SD rats exhibit patterns of drug responses in this model that are optimal for examining profiles of putative atypical antipsychotics. Show less

In the present study, separate squads of rats were trained to discriminate either the dopamine D3 receptor preferring ligand 7-hydroxy-2-(di-N-propylamino)-tetralin (7-OH-DPAT) (0.03 mg/kg) from saline, or D-amphetamine (0.3 mg/kg) from saline using a standard operant schedule (FR10 schedule reinforcement). Following stable acquisition of responding, tests of generalisation and antagonism were conducted. A number of dopamine agonists having high dopamine D2-like receptor (D2, D3 or D4) affinity… Show more

In the present study, separate squads of rats were trained to discriminate either the dopamine D3 receptor preferring ligand 7-hydroxy-2-(di-N-propylamino)-tetralin (7-OH-DPAT) (0.03 mg/kg) from saline, or D-amphetamine (0.3 mg/kg) from saline using a standard operant schedule (FR10 schedule reinforcement). Following stable acquisition of responding, tests of generalisation and antagonism were conducted. A number of dopamine agonists having high dopamine D2-like receptor (D2, D3 or D4) affinity generalised to the 7-OH-DPAT, but not amphetamine, cue. The dopamine D2/3 receptor agonist SKF38393 showed no generalisation to either drug cue. Subsequent correlational analysis suggested that this effect was most likely mediated through the dopamine D3 receptor. The dopamine D2/3 receptor antagonist raclopride significantly attenuated both cues. The failure of these drugs to generalise to amphetamine, suggest that there is little involvement of the dopamine D3 receptor subtype in mediating its discriminative stimulus properties. Show less

Prepulse inhibition (PPI) of an acoustic startle response is impaired in schizophrenics. PPI can also be studied in the rat, and is impaired by dopamine (DA) D2/3 receptor agonists such as apomorphine. This disruption is reversed by DA antagonists, leading to proposals that this approach may be a useful means to identify novel antipsychotics. There is also evidence to suggest a role of serotonergic (5-HT) and glutamatergic systems in schizophrenia, and accordingly PPI can be disrupted by the… Show more

Prepulse inhibition (PPI) of an acoustic startle response is impaired in schizophrenics. PPI can also be studied in the rat, and is impaired by dopamine (DA) D2/3 receptor agonists such as apomorphine. This disruption is reversed by DA antagonists, leading to proposals that this approach may be a useful means to identify novel antipsychotics. There is also evidence to suggest a role of serotonergic (5-HT) and glutamatergic systems in schizophrenia, and accordingly PPI can be disrupted by the 5-HT2 agonist DOI, and the non-competitive NMDA antagonist, dizocilpine. In the present study we have examined the effect of four antipsychotic drugs, haloperidol (0.1-0.3 mg/kg), raclopride (0.03-0.3 mg/kg), risperidone (0.3-3 mg/kg) and clozapine (0.0001-10 mg/kg), against the PPI disruptions induced by apomorphine (0.5 mg/kg), DOI (3 mg/kg) and dizocilpine (0.15 mg/kg). Furthermore, these drugs have been examined for their ability to restore a PPI deficit produced by housing rats under conditions of social isolation. All drugs except clozapine reversed an apomorphine-induced disruption. However, clozapine and risperidone, but not raclopride and haloperidol, reversed a DOI-induced disruption. Only risperidone was effective in restoring a PPI deficit produced by dizocilpine. In contrast to the drug-induced disruptions which were differentially sensitive to the various neuroleptics, isolation-induced disruptions were restored by each drug. These results support the idea that non-drug induced disruptions of PPI, such as social isolation, may be a more viable approach to identify novel antipsychotics. Show less

In the present study we have examined the effect of varying three prepulse parameters (prepulse intensity, prepulse duration, prepulse-pulse interval) on the level of prepulse inhibition (PPI) in Lister hooded, Wistar and Sprague-Dawley rats. The results indicate that each strain showed subtle differences in sensitivity to the prepulse. For instance, Sprague-Dawley and Lister hooded rats showed PPI to prepulses of lower saliency compared to Wistar rats. Optimal prepulse parameters were selected… Show more

In the present study we have examined the effect of varying three prepulse parameters (prepulse intensity, prepulse duration, prepulse-pulse interval) on the level of prepulse inhibition (PPI) in Lister hooded, Wistar and Sprague-Dawley rats. The results indicate that each strain showed subtle differences in sensitivity to the prepulse. For instance, Sprague-Dawley and Lister hooded rats showed PPI to prepulses of lower saliency compared to Wistar rats. Optimal prepulse parameters were selected for each strain to examine the effects of apomorphine and phencyclidine on PPI. Further inter-strain differences were noted; apomorphine (0.1-1 mg/kg) increased startle amplitude in Lister hooded and Sprague-Dawley, but not Wistar rats. PPI was attenuated in each strain by apomorphine pretreatment. In a final series of experiments, phencyclidine disrupted PPI in each strain, although with greater potency in the Lister hooded rats. A marked behavioural syndrome was seen at phencyclidine doses that disrupted PPI. It is concluded that rat strain and prepulse parameters are important variables in studying drug effects on PPI. Show less