Characterization of the V1a antagonist, JNJ-17308616, in rodent models of anxiety-like behavior.

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.

Comparison of the V1b antagonist, SSR149415, and the CRF1 antagonist, CP-154,526, in rodent models of anxiety and depression.

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.

Characterization of the nociceptin receptor (ORL-1) agonist, Ro64-6198, in tests of anxiety across multiple species.

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.

Centrally administered hemokinin-1 (HK-1), a neurokinin NK1 receptor agonist, produces substance P-like behavioral effects in mice and gerbils.

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.

The antidepressant-like effects of neurokinin NK1 receptor antagonists in a gerbil tail suspension test.

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.

Comparison of apomorphine, amphetamine and dizocilpine disruptions of prepulse inhibition in inbred and outbred mice strains.

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.

Environmental enrichment and isolation rearing in the rat: effects on locomotor behavior and startle response plasticity.

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.

The genetic liability to stress and postweaning isolation have a competitive influence on behavioral organization in rats.

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.

The dopamine D(1) receptor agonist SKF-82958 serves as a discriminative stimulus in the rat.

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.

The dopamine D2, but not D3 or D4, receptor subtype is essential for the disruption of prepulse inhibition produced by amphetamine in mice.

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.

Is there a critical developmental 'window' for isolation rearing-induced changes in prepulse inhibition of the acoustic startle response?

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.

Reduced synaptophysin immunoreactivity in the dentate gyrus of prepulse inhibition-impaired isolation-reared rats.

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.

M100907, a serotonin 5-HT2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in Sprague-Dawley and Wistar rats.

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. Furthermore, this interaction occurs in at least two rat strains.

Dopamine agonist-induced hypothermia and disruption of prepulse inhibition: evidence for a role of D3 receptors?

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.

Aging effects on the startle response and startle plasticity in Fischer F344 rats.

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.

Effects of isolation rearing on startle reactivity, habituation, and prepulse inhibition in male Lewis, Sprague-Dawley, and Fischer F344 rats.

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.

Discrepant findings of clozapine effects on prepulse inhibition of startle: is it the route or the rat?

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.

Investigations into the nature of a 7-OH-DPAT discriminative cue: comparison with D-amphetamine.

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.

Reversal of dizocilpine-induced disruption of prepulse inhibition of an acoustic startle response by the 5-HT2 receptor antagonist ketanserin.

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.

Examination of drug-induced and isolation-induced disruptions of prepulse inhibition as models to screen antipsychotic drugs.

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.