"Early" and "late" effects of sustained haloperidol on apomorphine- and phencyclidine-induced sensorimotor gating deficits.

Both dopamine (DA) agonists and NMDA antagonists produce prepulse inhibition (PPI) deficits in rats that model PPI deficits in schizophrenia patients. While DA agonist effects on PPI are reversed by acute treatment with either "typical" high-potency D2 DA antagonists or "atypical" antipsychotics, PPI deficits produced by phencyclidine (PCP) are preferentially reversed by acute treatment with "atypical" antipsychotics. Acute effects of antipsychotics may not accurately model the more clinically relevant effects of these drugs that emerge after several weeks of continuous treatment. In the present study, sustained treatment with haloperidol via subcutaneous minipumps blocked the PPI-disruptive effects of apomorphine and attenuated the PCP-induced disruption of PPI. Restoration of PPI in apomorphine-treated rats was evident within the first week of sustained haloperidol administration. A partial reversal of PCP effects on PPI did not develop until the second week of sustained haloperidol treatment, followed a fluctuating course, but remained significant into the seventh week of sustained haloperidol administration. The delayed emergence of anti-PCP effects of haloperidol suggests that the brain substrates responsible for the DAergic and NMDA regulation of PPI are differentially sensitive to acute and chronic effects of antipsychotics.     

Time course of the attenuation effect of repeated antipsychotic treatment on prepulse inhibition disruption induced by repeated phencyclidine treatment

Antagonism of prepulse inhibition (PPI) deficits produced by psychotomimetic drugs has been widely used as an effective tool for the study of the mechanisms of antipsychotic action and identifying potential antipsychotic drugs. Many studies have relied on the acute effect of a single administration of antipsychotics, whereas patients with schizophrenia are treated chronically with antipsychotic drugs. The clinical relevance of acute antipsychotic effect in this model is still an open question. In this study, we investigated the time course of repeated antipsychotic treatment on persistent PPI deficit induced by repeated phencyclidine (PCP) treatment. After a baseline test with saline, male Sprague-Dawley rats were repeatedly injected with either vehicle, haloperidol (0.05 mg/kg), clozapine (5.0 or 10.0 mg/kg), olanzapine (2.0 mg/kg), risperidone (1.0 mg/kg) or quetiapine (10 mg/kg), followed by PCP (1.5 mg/kg, sc) and tested for PPI once daily for 6 consecutive days. A single injection of PCP disrupted PPI and this effect was maintained with repeated PCP injections throughout the testing period. Acute clozapine, but not other antipsychotic drugs, attenuated acute PCP-induced PPI disruption at both tested doses. With repeated treatment, clozapine and quetiapine maintained their attenuation, while risperidone enhanced its effect with a significant reduction of PCP-induced disruption toward the end of treatment period. In contrast, repeated haloperidol and olanzapine treatments were ineffective. The PPI effects of these drugs were more conspicuous at a higher prepulse level (e.g. 82 dB) and were dissociable from their effects on startle response and general activity. Overall, the repeated PCP-PPI model appears to be a useful model for the study of the time-dependent antipsychotic effect, and may help identify potential treatments that have a quicker onset of action than current antipsychotics.     

The atypical antipsychotic,remoxipride, blocks phencyclidine-induced disruption of prepulse inhibition in the rat

The effect of various typical (haloperidol) and atypical (clozapine, raclopride, remoxipride) antipsychotics on phencyclidine (PCP)-induced disruption of sensorimotor gating was tested in rats using an acoustic startle paradigm. Clozapine (4–40 µmol/kg), haloperidol (1–5 µmol/kg) and raclopride (1–12 µmol/kg) failed to reverse PCP-induced disruption of prepulse inhibition (PPI) of the acoustic startle response. In contrast, remoxipride (12–60 µmol/kg) caused a dose-dependent block of this effect. PCP-induced disruption of PPI is a widely accepted animal model of a corresponding behavioural deficit observed in schizophrenia although little evidence has been presented that it is in fact sensitive to antipsychotic agents. The present results indicate that remoxipride behaves in a unique way in this model compared to clozapine, haloperidol and raclopride.     

Typical but not "atypical" antipsychotic effects on startle gating deficits in prepubertal rats

RATIONALE: Dopamine (DA) agonists and NMDA antagonists disrupt sensorimotor gating in rats, as measured by a loss of prepulse inhibition of the startle reflex. These effects are used in predictive models for antipsychotic efficacy: clinically "typical" and "atypical" antipsychotics restore PPI in adult rats treated with DA agonists such as apomorphine (APO), while clinically "atypical" antipsychotics restore PPI in rats treated with NMDA antagonists such as phencyclidine (PCP). We previously reported that the PPI disruptive effects of both APO and PCP are evident in 16- to 18-day-old rat pups, suggesting that the brain substrates for these effects are functional very early in development. OBJECTIVE: In the present study we assessed the developmental patterns of antipsychotic effects in these measures. METHODS: The PPI-disruptive effects of APO and PCP, and their antagonism by the typical antipsychotic haloperidol, and the atypical antipsychotic quetiapine, were assessed across development in Sprague-Dawley rats. RESULTS: Similar to the pattern seen in adults, both haloperidol and quetiapine opposed APO-induced PPI deficits in 16- to 19-day-old rat pups. However, the "atypical" antipsychotic quetiapine did not oppose PCP-induced PPI deficits in pups or prepubertal (45 day) adolescents, but did oppose these PCP effects in postpubertal rats. CONCLUSIONS: While brain substrates mediating the PPI-disruptive effects of DA agonists and NMDA antagonists are functional early in development, some physiological event associated with puberty is a necessary condition for the "atypical antipsychotic profile" in this predictive model.     

The effects of subchronic haloperidol on intact and dizocilpine-disrupted sensorimotor gating

Rationale: Reversal of deficits in prepulse inhibition (PPI) of the startle reflex in rats is considered a preclinical screen for potential antipsychotics. Whereas acutely administered antipsychotics consistently reverse apomorphine-induced deficits in PPI, some antipsychotics, including haloperidol, are unable to reverse deficits in PPI produced by non-competitive NMDA antagonists such as phencyclidine or dizocilpine (MK-801). Acute administration of antipsychotics tends to facilitate baseline PPI. However, the effect is generally not large enough in magnitude nor reliable enough to be considered a useful preclinical screen for antipsychotic activity. Objective: Because the clinical effects of antipsychotics typically require subchronic administration, this study tested the hypothesis that reversal of NMDA antagonist-induced deficits in PPI by antipsychotics require subchronic administration. A second aim of this study was to determine if subchronic administration of an antipsychotic produces a more potent facilitation of baseline PPI than acute administration. Methods: Rats received a subcutaneous injection of 0, 0.025, 0.1 or 0.5 mg/kg haloperidol for 16 consecutive days. On day 16, half the rats in each haloperidol dose group received a second subcutaneous injection consisting of either dizocilpine (0.1 mg/kg) or saline. Results: None of the haloperidol doses tested had a significant effect on baseline PPI. The 0.1 mg/kg dose of haloperidol diminished but did not completely reverse dizocilpine-induced disruption of PPI. The other doses had no significant effect. Conclusions: These results suggest that time course factors may partially modify the effects of haloperidol on dizocilpine-induced disruption of PPI but not its effect on baseline PPI. Received: 4 December 1998 / Final version: 19 April 1999     

Clozapine enhances disruption of prepulse inhibition after sub-chronic dizocilpine- or phencyclidine-treatment in Wistar rats

Sensitisation (i.e. progressive enhancement) of behavioural abnormalities induced by repeated treatment with non-competitive NMDA receptor antagonists in animals is considered an animal model for schizophrenia. Here, male Wistar rats were treated for 11 days with either dizocilpine (0.1 mg/kg), phencyclidine (PCP, 2 mg/kg), or saline and tested for prepulse inhibition (PPI) of the acoustic startle response (ASR). The aims of this study were twofold: First, we tested whether sensitisation of PPI deficits previously found in Sprague-Dawley rats were also found in Wistar rats, and, second, whether these effects can be ameliorated by the atypical antipsychotic clozapine. PPI is a paradigm for the assessment of sensorimotor gating (and its deficits) and is impaired in schizophrenic patients. After the sub-chronic treatment the rats were tested drug-free (day 12), and on the following days after drug challenge by PCP (2 mg/kg), combinations of PCP (2 mg/kg) and clozapine (5 and 10 mg/kg), or clozapine (5 mg/kg) alone. PPI was significantly reduced by both NMDA receptor antagonists. This effect was not further enhanced by the daily treatment. Startle magnitude was increased after eight days of dizocilpine-treatment only, indicating sensitisation of startle-potentiation by this drug. Testing the rats drug-free on day 12 revealed enhanced PPI and reduced startle (compared to the matching test on day 0) irrespective of previous treatment. Drug challenge with PCP (2 mg/kg) again reduced PPI in all groups. Clozapine (5 and 10 mg/kg) failed to antagonise the PPI-disruptive effects of PCP and even enhanced the PCP-induced PPI-deficits in rats pretreated with PCP or dizocilpine. These findings suggest: (1) that PPI and startle are influenced differently by non-competitive NMDA receptor antagonists, (2) that PCP and dizocilpine reduce PPI in Wistar rats, but do not lead to a sensitisation of this effect; and (3) that under the present schedule of treatments, the antipsychotic compound clozapine does not antagonise but rather enhances PPI-disruptive effects of non-competitive NMDA receptor antagonists, pointing towards a complex interaction of the brain processes underlying the action of psychotomimetic and atypical antipsychotic drugs.     

Iloperidone reduces sensorimotor gating deficits in pharmacological models, but not a developmental model, of disrupted prepulse inhibition in rats

Iloperidone is a novel atypical antipsychotic which acts as a broad spectrum dopamine/serotonin/norepinephrine receptor antagonist. To compare iloperidone behaviorally to other known antipsychotics, we evaluated the drug in three pharmacological models and one developmental model of disrupted prepulse inhibition (PPI) in rats. Firstly, 0.5 mg/kg apomorphine induced PPI deficits that were prevented by pretreatment with iloperidone (1 and 3 mg/kg). Secondly, treatment with the N-methyl-D-aspartate (NMDA)-receptor antagonist phencyclidine (PCP) produced robust deficits in PPI. Both doses of iloperidone (1 and 3 mg/kg) prevented the PPI-disruptive effects of treatment with 1 mg/kg PCP. Thirdly, treatment with the alpha1-adrenoceptor agonist cirazoline (0.6 mg/kg) disrupted PPI, and produced a concurrent large increase in startle magnitude. A relatively low dose of iloperidone (0.3 mg/kg) prevented cirazoline-induced PPI deficits, independent of its effects on startle magnitude. Finally, iloperidone (1 mg/kg) did not reverse PPI deficits in the isolation-rearing model of schizophrenia. These results indicate that iloperidone exerts behavioral effects in pharmacological models of disrupted sensorimotor gating consistent with "atypical" antipsychotics, mediated by antagonism of dopaminergic and noradrenergic receptors. The absence of effect in isolation-reared rats may be due to the relatively small effect size of isolation rearing on PPI or dose of iloperidone.     

Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine

Prepulse inhibition (PPI) of the startle reflex provides an operational measure of sensorimotor gating. Deficits in PPI are observed in schizophrenia patients and can be modelled in animals by administration of noncompetitive NMDA antagonists such as phencyclidine (PCP) or dizocilpine (MK-801). Previous studies indicate that the atypical antipsychotic clozapine restores PPI in PCP-treated animals while the typical antipsychotic haloperidol does not. Olanzapine (LY170053) is a novel putative atypical antipsychotic that shares many pharmacological and behavioral properties with clozapine. The present study assessed the ability of olanzapine (0, 1.25, 2.5, 5.0 or 10.0 mg/kg) to antagonize deficits in PPI produced by PCP (1.5 mg/kg) and dizocilpine (0.1 mg/kg). At the two highest doses, olanzapine significantly increased PPI in PCP- and dizocilpine-treated animals without affecting PPI or baseline startle reactivity by itself. These results support the notion that olanzapine is functionally similar to clozapine and may have utility as an atypical antipsychotic agent.     

Ontogeny of phencyclidine and apomorphine-induced startle gating deficits in rats

NMDA antagonists and dopamine (DA) agonists produce neuropathological and/or behavioral changes in rats that may model specific abnormalities in schizophrenia patients. In adult rats, NMDA antagonists and DA agonists disrupt sensorimotor gating-measured by prepulse inhibition (PPI)-modeling PPI deficits in schizophrenia patients. In addition, high doses of NMDA antagonists produce limbic system pathology that may model neuropathology in schizophrenia patients. We examined these behavioral and neuropathological models across development in rats. Both the NMDA antagonist phencyclidine (PCP) and the DA agonist apomorphine disrupted PPI in 16 day pups, demonstrating early developmental functionality in substrates regulating these drug effects on PPI. In contrast, PCP neurotoxicity was evident only in adult rats. Brain mechanisms responsible for the PCP disruption of PPI, and PCP-induced neurotoxicity, are dissociable across development.     

Reversal of PCP-induced learning and memory deficits in the Morris’ water maze by sertindole and other antipsychotics

RATIONAL: In humans, the N-methyl-D-aspartate antagonist phencyclidine (PCP) induces behavioral changes that mimic schizophrenia symptoms, including positive and negative symptoms as well as cognitive deficits. In clinic, the cognitive deficits are closely associated with functional outcome. Thus, improvement of cognition may have high impact on patients' daily life. OBJECTIVE: In the present study, three second-generation antipsychotics (sertindole, risperidone, and clozapine) as well as the classical antipsychotic haloperidol were tested for the ability to reverse PCP-induced cognitive deficits in the Morris' water maze. RESULTS: The second-generation antipsychotics reversed the PCP-induced cognitive impairment: sertindole (0.63-2.5 mg/kg, s.c.), risperidone (0.04 mg/kg, s.c.; whereas 0.08 and 0.16 mg/kg were without significant effect), and clozapine (0.63 mg/kg, s.c.; while 1.3 mg/kg was without significant effect). The significant effect of sertindole was observed from day 2 onwards, while clozapine and risperidone only had significant effect at day 3. The classical antipsychotic haloperidol (0.010-0.020 mg/kg, s.c.) was ineffective. No compounds influenced swimming speed at the doses used, indicating that motor function was preserved. CONCLUSION: These results confirm that repeated PCP administration induces marked cognitive deficits. Further, second-generation antipsychotics like sertindole, clozapine, and risperidone within a certain, often narrow, dose range are able to reverse the impairment and thus might improve cognitive deficits in schizophrenic patients, whereas classical compounds like haloperidol lack this effect. The receptor mechanisms involved in the reversal of PCP's disruptive effect are discussed and likely include a delicate balance between effects on dopamine D(2), 5-HT(2A/6), alpha-adrenergic, muscarinic, and histaminergic H(1) receptors.     

Seroquel, clozapine and chlorpromazine restore sensorimotor gating in ketamine-treated rats

Sensorimotor gating of the startle reflex – measured by prepulse inhibition (PPI) – is impaired in schizophrenia patients and in rats treated with either dopamine (DA) agonists or with N-methyl-D-aspartate (NMDA) antagonists. While both typical and atypical antipsychotics restore PPI in DA agonist-treated rats, studies thus far have demonstrated that only atypical antipsychotics restore PPI in rats treated with NMDA antagonists. This model for predicting atypical antipsychotic properties has been studied extensively in rats, and there is interest in moving these studies into humans, where the NMDA antagonist ketamine is also reported to significantly reduce PPI. In anticipation of such studies, and to facilitate the use of this model in humans, we examined the effects of high and low potency typical antipsychotics (haloperidol and chlorpromazine), the atypical antipsychotic clozapine, and the putative atypical antipsychotic, Seroquel, on ketamine-disrupted PPI in rats, across a range of ketamine that produced submaximal, as well as maximal disruptions of PPI. Ketamine dose-dependently reduced PPI, and this effect was significantly opposed by Seroquel, clozapine and chlorpromazine, but not haloperidol. The effects of chlorpromazine on ketamine-disrupted PPI demonstrate that the ability of antipsychotics to restore PPI in NMDA antagonist-treated rats is not specific to clinically atypical antipsychotics. Receptor properties shared by Seroquel, clozapine and chlorpromazine, but not haloperidol, may implicate critical substrates in the NMDA antagonist-induced disruption of PPI. Received: 31 December 1997/Final version: 11 March 1998     

Differential effects of acute and subchronic clozapine and haloperidol on phencyclidine-induced decreases in voluntary sucrose consumption in rats

Prior exposure to the psychotomimetic drug phencyclidine (PCP) decreases voluntary sucrose consumption in rats. This may be indicative of reduced reward function, a phenomenon associated with negative schizophrenic symptomatology. Given that atypical antipsychotics have been shown to ameliorate negative symptoms of schizophrenia more effectively than typical neuroleptics, this effect should be reversed by clozapine but not haloperidol. PCP (15 mg/kg) or saline was administered 20 h prior to testing for voluntary sucrose consumption in non-deprived rats. In the acute experiments, rats were treated with clozapine (5 mg/kg), haloperidol (0.2 mg/kg), or vehicle 45 min prior to testing. In the subchronic experiments, rats were treated with clozapine (3 mg/kg, bid), haloperidol (0.5 mg/kg, bid), or vehicle for 10 days prior to PCP administration. Acute clozapine exacerbated the PCP-induced decrease in sucrose consumption without altering water consumption. Acute haloperidol produced an overall decrease in sucrose consumption in both PCP-pretreated and control groups. Subchronic treatment with clozapine, but not haloperidol, reversed PCP-induced decreases in sucrose consumption. The synergistic effect of acute clozapine and PCP may reflect a PCP-induced increase in the reward-reducing properties of CLZ, normally seen only at higher doses. The observation that subchronic clozapine, but not haloperidol, reversed PCP-induced decreases in sucrose consumption supports the hypothesis that this effect of PCP represents a plausible animal model for negative schizophrenic symptomatology.     

Effect of acute and chronic olanzapine treatment on phencyclidine-induced behavioral sensitization in rats with neonatal dopamine loss

In agreement with previous work, adult rats given selective lesions to dopamine (DA)-containing neurons as neonates exhibited a greater behavioral sensitization to repeated phencyclidine (PCP) treatment in comparison to sham-lesioned controls. Acute administration of olanzapine (1-5 mg/kg ip) or clozapine (15 mg/kg ip) decreased sensitized PCP-induced activity in both lesioned and control animals. Acute haloperidol (0.5 mg/kg ip) had no impact on PCP responsiveness in lesioned animals, but significantly antagonized PCP effects in sham-lesioned controls. Ketanserin, a selective 5-HT(2A)/5-HT(2C)-receptor antagonist, significantly reduced PCP activation in both lesioned and control rats, suggesting that the efficacy of atypical antipsychotics against PCP-induced sensitized responses may be mediated by one of the 5-HT(2)-receptor subtypes. A 6-week chronic regimen of orally administered olanzapine, clozapine, or haloperidol failed to block the sensitization induced by repeated PCP exposure. However, a 10-month oral olanzapine treatment significantly blunted the behavioral sensitization to repeated PCP exposure in lesioned animals, even after withdrawal from chronic olanzapine for more than 3 weeks. A 10-month oral haloperidol treatment had no effect on the sensitization induced by repeated PCP dosing. The persistent effect of chronic olanzapine administration on PCP sensitization may be relevant to the chronic therapeutic efficacy of atypical antipsychotics treating schizophrenia-a clinical syndrome linked to enhanced sensitivity to N-methyl-d-aspartate (NMDA)-receptor antagonists.     

Increased impulsivity and disrupted attention induced by repeated phencyclidine are not attenuated by chronic quetiapine treatment

Atypical antipsychotic medications differ in how effectively they attenuate cognitive and other deficits in schizophrenia. The present study aimed to explore whether quetiapine, an atypical antipsychotic medication, would reverse disruptions of performance in the 5-choice serial reaction time task (5-CSRTT), a test of attention and impulsivity, induced by repeated administration of the psychotomimetic phencyclidine (PCP). In confirmation of previous findings, repeated PCP administration (2 mg/kg, s.c., 30 min before behavioral testing, for 2 consecutive days, followed by a 2-week PCP-free period and then 5 consecutive days of PCP treatment) increased premature responding (impulsivity), decreased accuracy (attention), and increased response latencies (processing speed) and timeout responding (impulsivity/cognitive inflexibility). Chronic quetiapine (5 or 10 mg/kg/day, s.c.) did not attenuate these PCP-induced disruptions in performance, while at the highest dose used, quetiapine disrupted 5-CSRTT performance in the absence of PCP treatment and tended to exacerbate the PCP-induced increase in premature responding. Considering that clozapine, another atypical antipsychotic, was shown previously to reverse PCP-induced deficits in the same task [Amitai N, Semenova S, Markou A. Cognitive-disruptive effects of the psychotomimetic phencyclidine and attenuation by atypical antipsychotic medications in rats. Psychopharmacology (Berl) 2007;193:521-37], the present findings demonstrate differences between clozapine and quetiapine in their effectiveness on schizophrenia-like cognitive deficits and impulsivity that may be attributable to their different receptor affinity profiles.     

Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review

RATIONALE: Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. Similar deficits in PPI are produced in rats by pharmacological or developmental manipulations. These experimentally induced PPI deficits in rats are clearly not animal models of schizophrenia per se, but appear to provide models of sensorimotor gating deficits in schizophrenia patients that have face, predictive, and construct validity. In rodents, disruptions in PPI of startle are produced by: stimulation of D2 dopamine (DA) receptors, produced by amphetamine or apomorphine; activation of serotonergic systems, produced by serotonin (5-HT) releasers or direct agonists at multiple serotonin receptors; and blockade of N-methyl-D-aspartate (NMDA) receptors, produced by drugs such as phencyclidine (PCP). Accordingly, dopaminergic, serotonergic, and glutamatergic models of disrupted PPI have evolved and have been applied to the identification of potential antipsychotic treatments. In addition, some developmental manipulations, such as isolation rearing, have provided non-pharmacological animal models of the PPI deficits seen in schizophrenia. OBJECTIVE: This review summarizes and evaluates studies assessing the effects of systemic drug administrations on PPI in rats. METHODS: Studies examining systemic drug effects on PPI in rats prior to January 15, 2001 were compiled and organized into six annotated appendices. Based on this catalog of studies, the specific advantages and disadvantages of each of the four main PPI models used in the study of antipsychotic drugs were critically evaluated. RESULTS: Despite some notable inconsistencies, the literature provides strong support for significant disruptions in PPI in rats produced by DA agonists, 5-HT2 agonists, NMDA antagonists, and isolation rearing. Each of these models exhibits sensitivity to at least some antipsychotic medications. While the PPI model based on the effects of direct DA agonists is the most well-validated for the identification of known antipsychotics, the isolation rearing model also appears to be sensitive to both typical and atypical antipsychotics. The 5-HT PPI model is less generally sensitive to antipsychotic medications, but can provide insight into the contribution of serotonergic systems to the actions of newer antipsychotics that act upon multiple receptors. The deficits in PPI produced by NMDA antagonists appear to be more sensitive to clozapine-like atypical antipsychotics than to typical antipsychotics. Hence, despite some exceptions to this generalization, the NMDA PPI model might aid in the identification of novel or atypical antipsychotic medications. CONCLUSIONS: Studies of drug effects on PPI in rats have generated four distinctive models that have utility in the identification of antipsychotic medications. Because each of these models has specific advantages and disadvantages, the choice of model to be used depends upon the question being addressed. This review should help to guide such decisions.     

Effects of novel antipsychotics with mixed D(2) antagonist/5-HT(1A) agonist properties on PCP-induced social interaction deficits in the rat

Considerable interest has arisen in identifying antipsychotic agents with improved efficacy against negative symptoms, such as social withdrawal. In rats, a social interaction deficit can be induced by the NMDA antagonist phencyclidine (PCP). Here, we examined the effects of antipsychotics, reported to exert dual 5-HT(1A)/D(2) actions, on PCP-induced social interaction deficits. Drugs were administered daily for 3 days in combination with either vehicle or PCP (2.5mg/kg, SC) and social interaction was measured on the last day of drug treatment. Pairs of unfamiliar rats receiving the same treatment were placed in a large open field for 10 min and the number of social behaviors were scored. The results indicate that: (1) PCP significantly reduced social interaction by over 50% compared with vehicle-treated controls; (2) haloperidol (0.0025-0.16 mg/kg, SC) and clozapine (0.04-10mg/kg, IP) did not reverse PCP-induced social interaction deficits; (3) the substituted benzamide remoxipride reversed PCP-induced deficits at 0.63 and 2.5mg/kg (4) the 5-HT(1A) agonist 8-OH-DPAT was inactive (at 0.01-0.63 mg/kg, SC); (5) among compounds reported to exert dual 5-HT(1A)/D(2) actions, SSR181507 (at 0.16 mg/kg, SC) and aripiprazole (at 0.04 and 0.16 mg/kg, IP), but not ziprasidone (0.04-2.5mg/kg, IP), SLV313 (0.0025-0.16 mg/kg, SC) or bifeprunox (0.01-0.63 mg/kg, IP), significantly reversed PCP-induced social interaction deficits; and (6) the 5-HT(1A) receptor antagonist WAY100635 blocked the effects of SSR181507 and aripiprazole. These findings indicate that the balance of activity at 5-HT(1A) and D(2) receptors profoundly influences the activity of antipsychotics in this model of social withdrawal, and their potential benefit on at least some of the negative symptoms of schizophrenia.     

Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of clozapine, but not haloperidol

This study was undertaken to examine the effects of subsequent administration of antipsychotic drugs (clozapine and haloperidol) on cognitive deficits in mice after repeated administration of phencyclidine (PCP). In the novel object recognition test, repeated administration of PCP (10 mg/kg) significantly decreased exploratory preference in the retention test session but not in the training test session. PCP-induced deficits were significantly improved by subsequent subchronic (2 weeks) administration of clozapine (5 mg/kg), but not haloperidol (0.1 mg/kg). These findings suggest that PCP-induced cognitive deficits using the novel object recognition test may be a potential animal model of atypical antipsychotic activity.     

The Effects of dizocilpine and phencyclidine on prepulse inhibition of the acoustic startle reflex and on prepulse-elicited reactivity in C57BL6 mice.

Prepulse inhibition (PPI) of the acoustic startle response refers to the reduction in startle reaction to a startle-eliciting stimulus when it is shortly preceded by a subthreshold prepulse stimulus. Here, we evaluated the possible effects on prepulse-elicited reactivity by dizocilpine (MK-801) and phencyclidine (PCP) in the PPI of acoustic startle paradigm in C57BL6/J mice. The aim was to ascertain whether these two drugs would affect prepulse-elicited reactivity in a manner similar to apomorphine, which enhances prepulse-elicited reactivity at doses that disrupt PPI. In two dose-response studies, we showed that both drugs exhibited a tendency to attenuate prepulse-elicited reaction at higher doses when PPI was severely disrupted. On the other hand, at lower doses when PPI was marginally disrupted, reaction to the prepulse, if anything, tended to increase. It is concluded that PPI disruption induced by noncompetitive NMDA receptor antagonists can be distinguished from apomorphine-induced PPI disruption by their concomitant effects on prepulse-elicited reactivity. Our data support the suggestion that dopamine receptor agonists and NMDA receptor antagonists disrupt PPI via interference with distinct neural pathways or neuronal systems.     

Olanzapine and clozapine but not haloperidol reverse subchronic phencyclidine-induced functional hyperactivity of N-methyl-D-aspartate receptors in pyramidal cells of the rat medial prefrontal cortex

In the present study, we have investigated and compared the ability of olanzapine, clozapine and haloperidol to modulate phencyclidine (PCP)-induced effect in pyramidal cells of the medial prefrontal cortex (mPFC) of rats using the techniques of intracellular recording and voltage-clamp. Subchronic treatment of rats with PCP (2 mg/kg, b.i.d., 7 days, 48-60 h withdrawal) produced: (1) a depolarized resting membrane potential, a decrease of slow after hyperpolarization (sAHP) and spike frequency adaptation, (2) a shift of the concentration response curve of N-methyl-D-aspartate (NMDA), but not (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), to the left, (3) a decrease of the paired pulse facilitation (PPF) with an increase of excitatory postsynaptic current variance (EPSC variance), and (4) a reduction of the blockade of NMDA response by in vitro application of PCP. Repeated treatment with either olanzapine or clozapine, but not haloperidol, completely prevented the aforementioned subchronic PCP-induced effects. The present results indicate that the atypical antipsychotic drugs (APDs) clozapine and olanzapine share a common property in preventing subchronic PCP-induced functional hyperactivity of NMDA receptors.     

Actions of novel antipsychotic agents on apomorphine-induced PPI disruption: influence of combined serotonin 5-HT1A receptor activation and dopamine D2 receptor blockade.

The dopamine D1/D2 agonist apomorphine (0.63 mg/kg) disrupted prepulse inhibition (PPI) of acoustic startle in rats, a model of sensorimotor gating deficits observed in schizophrenia. All current antipsychotics, which antagonize D2 receptors, prevent this apomorphine-induced deficit. A novel class of antipsychotics possesses, in addition to D2 antagonist property, various levels of 5-HT1A agonist activity. Considering that the latter itself produces PPI deficits, it appeared necessary to assess the potential of this novel class of antipsychotics to reverse apomorphine-PPI deficits. Potent D2 antagonists, like haloperidol (0.63-2.5 mg/kg), risperidone (0.63-10 mg/kg), and olanzapine (0.63-40 mg/kg) prevented apomorphine PPI disruption. The atypical antipsychotics, clozapine (40 mg/kg), nemonapride (0.01-2.5 mg/kg), ziprasidone (10 mg/kg), and aripiprazole (0.01 and 10 mg/kg), which all exhibit 5-HT1A agonist properties, reversed PPI deficits at some doses only, whereas the anti-dyskinetic agent sarizotan (0.16-10 mg/kg), an efficacious 5-HT1A agonist, did not. New generation antipsychotics with marked 5-HT1A agonist properties, such as SLV313 and SSR181507 (0.0025-10 mg/kg and 0.16-10 mg/kg, respectively) did not reverse these deficits whereas bifeprunox (0.04-2.5 mg/kg) did. To reveal the contribution of 5-HT1A agonist properties in the lack of effects of SLV313 and SSR181507, we pretreated rats with the 5-HT1A antagonist WAY100635 (0.63 mg/kg). Under these conditions, significant reversal of PPI deficit was observed, indicating that D2 antagonist properties of SLV313 and SSR181507 are now sufficient to overcome the disruptive effects of apomorphine. To summarize, antipsychotics possessing agonist efficacy at 5-HT1A receptors exhibit diverse profiles against apomorphine-induced PPI deficits, depending on the balance between D2 and 5-HT1A activities, suggesting that they may display distinct activity on some aspects of gating deficits in schizophrenic patients.