Repeated Phencyclidine Treatment Research Articles

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.

Multiple ‘hits’ during postnatal and early adulthood periods disrupt the normal development of sensorimotor gating ability in rats

In the present study, we evaluated a multiple-hit animal model of schizophrenia in an attempt to capture the complex interactions among various adverse developmental factors in schizophrenia. Sprague-Dawley rats were assigned to receive either repeated daily 3-h maternal separation for eight days (first 'hit') on postnatal days (PND) 3 to 10, and/or avoidance conditioning for six days (second 'hit') on PND 49-56, and/or repeated phencyclidine treatment (third 'hit', 3.0 mg/kg, sc) immediately after each daily avoidance conditioning. Prepulse inhibition (PPI) of acoustic startle reflex was assessed at late adolescence (PND 41-43) and early adulthood (PND 62-63). The change in %PPI from the adolescence phase to adulthood phase was used to index the maturation-related improvement of sensorimotor gating ability. Maternal separation, avoidance conditioning and PCP treatment had a complex three-way interaction on the functional improvement of sensorimotor gating. Maternal separation impaired PPI improvement preferentially in the saline rats that were not subjected to avoidance conditioning. Avoidance conditioning had no effect on PPI improvement in the non-maternally separated rats, but restored the maternal separation-induced disruption. However, this restoration effect was abolished by PCP treatment. The present study also identified a number of behavioral, emotional and learning abnormalities caused by these three developmental insults which may precede their interactive disruption of normal development of sensorimotor gating ability.

α 7 Nicotinic acetylcholine receptor activation prevents behavioral and molecular changes induced by repeated phencyclidine treatment

The core features of schizophrenia include deficits in cognitive processes, such as attention and working memory, subserved by the prefrontal cortex (PFC). These deficits are believed to involve deficient neurotransmission through NMDA receptors, particularly on parvalbumin-containing interneurons, and administration of the NMDA-antagonist phencyclidine (PCP) in rodents is a well validated model of such cognitive deficits. Here we show that repeated PCP treatment (10 mg/kg/day for 10 days) decreased the expression of parvalbumin and synaptophysin mRNA in the mouse PFC, which corresponds to changes seen in patients with schizophrenia. In addition, PCP increased the basal mRNA expression in the PFC of the activity-regulated cytoskeleton-associated protein (Arc), a molecule involved in synaptic plasticity. These molecular changes produced by PCP were accompanied by a behavioral impairment as determined in a modified Y-maze test. Polymorphisms in the α 7 nicotinic acetylcholine receptor (nAChR) gene have been linked to schizophrenia. Here we demonstrate that acute administration of the selective α 7 nAChR partial agonist SSR180711 dose-dependently reversed the behavioral impairment induced by PCP. Importantly, repeated co-administration of SSR180711 (3 mg/kg) with PCP prevented both the changes in parvalbumin, synaptophysin, and Arc mRNA expression in the PFC, and the behavioral impairment induced by PCP. These results are the first to demonstrate prevention of the deleterious effects induced by repeated PCP treatment. The behavioral and molecular effects of α 7 nAChR agonism in this model, particularly the prevention of a decline in parvalbumin mRNA expression, suggest an involvement of the α 7 nAChR not only in the symptomatic relief, but also the pathophysiology, of schizophrenia.

Clozapine Normalizes Prefrontal Cortex Dopamine Transmission in Monkeys Subchronically Exposed to Phencyclidine

The mechanism responsible for the therapeutic effects of the prototypical atypical antipsychotic drug, clozapine, is still not understood; however, there is persuasive evidence from in vivo studies in normal rodents and primates that the ability to elevate dopamine neurotransmission preferentially in the prefrontal cortex is a key component to the beneficial effects of clozapine in schizophrenia. Theoretically, such an effect of clozapine would counteract the deficient dopaminergic innervation of the prefrontal cortex that appears to be part of the pathophysiology of schizophrenia. We have previously shown that following repeated, intermittent administrations of phencyclidine to monkeys there is lowered prefrontal cortical dopamine transmission and impairment of cognitive performance that is dependent on the prefrontal cortex; these biochemical and behavioral changes therefore model certain aspects of schizophrenia. We now investigate the effects of clozapine on the dopamine projections to prefrontal cortex, nucleus accumbens, and striatum in control monkeys and in those withdrawn from repeated phencyclidine treatment, using a dose regimen of clozapine that ameliorates the cognitive deficits described in the primate phencyclidine (PCP) model. In normal monkeys, clozapine elevated dopamine turnover in all prefrontal cortical, but not subcortical, regions analyzed. In the primate PCP model, clozapine normalized dopamine (DA) turnover in the dorsolateral prefrontal cortex, prelimbic cortex, and cingulate cortex. Thus, the present data support the hypothesis that the therapeutic effects of clozapine in this primate model and perhaps in schizophrenia may be related at least in part to the restoration of DA tone in the prefrontal cortex.

(+) MK‐801 and Phencyclidine Induced Neurotoxicity do Not Cause Enduring Behaviours Resembling the Positive and Negative Symptoms of Schizophrenia in the Rat

Studies in rats and primates have demonstrated that repeated phencyclidine treatment can produce enduring cognitive deficits that may resemble the cognitive deficits seen in schizophrenia, suggesting that neurodegeneration resulting from NMDA-receptor dysfunction may be a valid model of schizophrenia. The purpose of the present experiments was to expand these findings and to determine if medium and high doses of the NMDA-antagonists phencyclidine and (+)MK-801 could produce permanent behavioural changes in animal tests with face validity for some aspects of the positive and negative symptoms of schizophrenia. Rats were treated with dose regimens of (+)MK-801 and phencyclidine known to produce mild and severe irreversible levels of neurotoxicity, and were tested 7 or 10 days after the last drug administration in the social interaction test and in standard activity cages. The rats did not show any enduring behavioural changes as a result of the treatment. The present study could therefore not provide additional evidence for the face validity of this model of schizophrenia.

Differential regulation of chromogranin A, chromogranin B and secretogranin II in rat brain by phencyclidine treatment.

Chromogranin A, chromogranin B and secretogranin II belong to the chromogranin family which consists of large protein molecules that are found in large dense core vesicles. Chromogranins are endoproteolytically processed to smaller peptides. This study was designed to elucidate the regulation of chromgranin expression by acute and subchronic phencyclidine administration. The behavioral syndrome produced by phencyclidine represents a pharmacological model for some aspects of schizophrenia [Jentsch and Roth (1999) Neuropsychopharmacology 20, 201-225]. Tissue concentrations of chromogranins were measured with specific radioimmunoassays. Alterations in secretogranin II gene expression were investigated by in situ hybridization. A single dose of phencyclidine (10mg/kg) led to a transient decrease in secretoneurin tissue levels in the prefrontal cortex after 4h followed by an increase in secretoneurin tissue levels after 12h. Repeated phencyclidine treatment (10mg/kg/day) for five days resulted in elevated secretoneurin levels in cortical areas whereas chromogranin A and chromogranin B tissue levels were unchanged. After the same treatment, a significant increase in the number of secretoneurin containing neurons was found in cortical layers II-III, and V-VI as revealed by immunocytochemistry. The increases in secretoneurin levels were paralleled by an increased number of secretogranin II messenger RNA containing neurons as well as by an increased expression of secretogranin II by individual neurons. The present study shows that secretoneurin II tissue concentration and secretogranin II messenger RNA expression is distinctly altered after acute and subchronic phencyclidine application. From these results we suggest that phencyclidine may induce synaptic alterations in specific brain areas and may contribute to a better understanding of synaptic dysfunction which may also occur in schizophrenia.

ChemInform Abstract: Neuropsychopharmacological Study on an Animal Model for Negative Symptom of Schizophrenia Induced by Repeated Phencyclidine Treatment

To develop an animal model for negative symptoms, in particular avolition, of schizophrenia, the effect of phencyclidine (PCP) on immobility (regarded as avolition) in the forced swimming test was investigated in mice, since PCP produces negative symptoms in humans. Unlike single, repeated treatment with PCP prolonged the immobility time in the forced swimming test 24 h after the final injection compared with saline treatment. The enhancing effect of PCP on the immobility persisted for 21 d after the withdrawal of the drug. Atypical antipsychotics attenuated the enhancing effect of PCP on the immobility. Since these attenuating effects were antagonized by a serotonin-S2 receptor agonist, (+/-)-2,5-dimethoxy-4-iodamphetamine (DOI), the effects may be mediated via serotonin-S2 receptors. In contrast with atypical antipsychotics, typical antipsychotics, antidepressants and anxiolytics had no effect. No functional changes in post-synaptic serotonin-S2 receptors were observed in PCP-treated mice following the forced swimming test. Serotonin utilization in the prefrontal cortex was increased, but dopamine utilization was decreased in PCP-treated mice showing the enhancement of immobility. The enhancing effect of PCP was significantly attenuated by D-cycloserine, an agonist for glycine binding site of N-methyl-D-aspartate (NMDA) receptor ionophore complex. Decreases of NMDA receptor function or of the cortical glutamate and glycine levels were observed in PCP-treated mice showing the enhancement of immobility. These results suggest that the enhancing effect of PCP on immobility is mediated by the imbalance of the cortical serotonergic, dopaminergic and glutamatergic systems and could be used as an animal model for negative symptoms of schizophrenia.

Repeated Phencyclidine Treatment Induces Negative Symptom-like Behavior in Forced Swimming Test in Mice: Imbalance of Prefrontal Serotonergic and Dopaminergic Functions

Repeated treatment with phencyclidine (PCP) prolonged the immobility time in a forced swimming test, compared with saline treatment, this behavioral change being regarded as avolition which is one of the negative symptoms of schizophrenia. In the present study, we investigated an involvement of serotonergic (5-HTergic) and dopaminergic systems in PCP-induced enhancement of immobility in mice, since an alteration in 5-HTergic and dopaminergic systems has been hypothesized in schizophrenia. The enhancing effect of PCP on the immobility in a forced swimming test was attenuated by clozapine, risperidone and olanzapine, which have serotonin (5-HT) and dopamine receptor antagonistic properties. These attenuating effects were significantly antagonized by a 5-HT2 receptor agonist, (±)-2,5-dimethoxy-4-iodamphetamine (DOI) without affecting the immobility itself. (−)Sulpiride at a low dose and methylphenidate reversed the PCP-induced enhancement of immobility whereas pimozide, chlorpromazine and levomepromazine had no effect. There was no difference in the frequency of DOI-induced head twitches, which are mediated via 5-HT2 receptors, between PCP- and saline-treated mice following the forced swimming test, indicating no functional changes in post-synaptic 5-HT2 receptors. 5-HT utilization in the prefrontal cortex was increased, but dopamine utilization was decreased in mice showing PCP-induced enhancement of immobility. These results suggest that the enhanced effect of PCP on the immobility is mediated by imbalance of 5-HTergic and dopaminergic systems in the prefrontal cortex and could be used as a model of the negative symptoms of schizophrenia.

Effects of repeated phencyclidine treatment on serotonin transporter in rat brain

Phencyclidine (PCP) is known to be an inhibitor of serotonin (5-HT) uptake and to increase serotonergic activity. The development of tolerance to serotonergic stereotyped behaviors induced by repeated PCP treatment and changes of 5-HT transporters were examined. Backpedalling was significantly reduced in frequency following 14 days PCP treatment (7.5 mg/kg per day). Furthermore, repeated PCP treatment decreased the equilibrium dissociation constant ( K d) of [ 3H]paroxetine binding to 5-HT transporters in whole brain excluding the cerebellum without any change of maximum number of binding sites ( B max). Single treatment with PCP failed to change binding parameters. These results indicate that repeated PCP treatment causes tolerance in serotonergic stereotyped behavior and increases affinity of 5-HT transporters for [ 3H]paroxetine binding. The increased affinity of 5-HT transporters could represent compensatory responses to chronic inhibition of 5-HT uptake by PCP.

Automation of the social interaction test by a video-tracking system: behavioural effects of repeated phencyclidine treatment

The social interaction test is a valuable behavioural model for testing anxiolytic and neuroleptic drugs. The test quantifies the level of social behaviour between pairs of rats and it is usually based on manual analysis of behaviour. Advances in computer technology have made it possible to track the movements of pairs of rats in an arena, and the present paper describes the automation of the social interaction test by the commercial video-tracking programme, the EthoVision ® system. The ability of the automated system to correctly measure the social behaviour of rats is demonstrated by determining a dose-response relationship in the social interaction test for phencyclidine, a psychotomimetic drug that reduces social behaviour between pairs of rats. These data are subsequently analysed by the manual and automated data-acquisition methods and the results are compared. The study shows that the automated data-acquisition method best describes the behavioural effects of phencyclidine in the social interaction test by the locomotor activity of the rats, how much time the rats spend in different sections of the testing arena, and the level of social behaviour. Correlation analysis of the results from the manual and automated data-acquisition methods shows that the social behaviour measured by the automated system corresponds correctly to the social behaviour measured by the manual analysis. The present study has shown that the automated data-acquisition method can quantify locomotor activity, how rats use a testing arena and the level of social behaviour between rats in the social interaction test. The system cannot distinguish between social and aggressive behaviours, and therefore the rats should be tested in an unfamiliar arena to reduce territorial behaviour. Taking this limitation into consideration, the social interaction test can be automated by this computer-based video-tracking system and can be used as a routine test for quantifying the effects of drugs on the social behaviour of rats.