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QUING CHANG, NEIL PATERSON, SCOTT F.DAVIS, C.NATHAN, COHRON , JENNIFER RICCIARDI, ADRIAN HACKETT, CAITLIN WETZLER, TALEEN HANANIA

Objective: Exposure to phencyclidine (PCP) has been used as an inducing condition in various animal models of schizophrenia. In the present studies, we assessed the effects of acute and subchronic PCP in a range of assays relevant to the cognitive impairments associated with schizophrenia and the negative symptoms of schizophrenia in rats. Methods: Subjects were exposed to vehicle or subchronic PCP at various doses (4-10 mg/kg/day) for 5-7 days followed by variable wash-out periods (1-5 days) in different studies. For the 5-choice serial reaction time task (5-CSRTT), delayed-match-to-position (DMTP) and cued reversal learning tasks, subjects had acquired the tasks prior to PCP exposure. For novel object recognition and social interaction, rats were naïve to testing prior to PCP exposure. PCP-induced deficits were assessed for sensitivity to the antipsychotic clozapine. Results: Subchronic PCP treatment induced deficits in episodic memory, cognitive flexibility and social functioning, assessed via the novel object recognition, cued reversal learning and social interaction tests. Nonetheless, sustained attention assessed via the 5-CSRTT and working memory assessed via the DMTP task, appeared insensitive to subchronic PCP exposure. Administration of clozapine attenuated PCP-induced deficits in novel object recognition and social interaction tests but clozapine alone induced deficits in the 5-CSRTT and DMTP tasks. Conclusions: These studies provide examples of deficits in cognitive and social function in rats that are at least partially sensitive to the atypical antipsychotic clozapine. Such models are likely relevant to the cognitive impairments (episodic memory) and negative symptoms (social functioning) of schizophrenia, and may be useful for the evaluation of novel antipsychotics. By contrast, the 5-CSRTT and DMTP task appeared insensitive to PCP treatment, but may be useful as a screen for cognitive deficits induced by antipsychotic medications, especially since such deficits decrease patient compliance.