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Cognitive-disruptive effects of the psychotomimetic phencyclidine and attenuation by atypical antipsychotic medications in rats

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Abstract

Background

Cognitive deficits in schizophrenia are severe and do not respond well to available treatments. The development and validation of animal models of cognitive deficits characterizing schizophrenia are crucial for clarifying the underlying neuropathology and discovery of improved treatments for such deficits.

Materials and methods

We investigated whether single and repeated administrations of the psychotomimetic phencyclidine (PCP) disrupt performance in the five-choice serial reaction time task (5-CSRTT), a test of attention and impulsivity. We also examined whether PCP-induced disruptions in this task are attenuated by atypical antipsychotic medications.

Results

A single injection of PCP (1.5–3 mg/kg, s.c., 30-min pre-injection time) had nonspecific response-depressing effects. Repeated PCP administration (2 mg/kg for two consecutive days followed by five consecutive days, s.c., 30-min pre-injection time) resulted in decreased accuracy, increased premature and timeout responding, and increased response latencies. The atypical antipsychotic medications clozapine, risperidone, quetiapine, and olanzapine and the typical antipsychotic medication haloperidol did not disrupt 5-CSRTT performance under baseline conditions except at high doses. The response depression induced by a single PCP administration was exacerbated by acute clozapine or risperidone and was unaffected by chronic clozapine. Importantly, chronic clozapine partially attenuated the performance disruptions induced by repeated PCP administration, significantly reducing both the accuracy impairment and the increase in premature responding.

Conclusions

Disruptions in 5-CSRTT performance induced by repeated PCP administration are prevented by chronic clozapine treatment and may constitute a useful animal model of some cognitive symptoms of schizophrenia.

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Acknowledgements

This work was supported by NIMH grant MH062527 to AM. NA was supported by individual Pre-Doctoral Fellowship 15DT-0048 from the Tobacco-Related Disease Research Program (TRDRP) of the State of California. The authors would like to thank Dr. Amanda Harrison and Professor Ian Stolerman for consulting us on establishing the five-choice serial reaction time task in our laboratory, Ms. Jessica Benedict and Ms. Chelsea Onifer for technical assistance, Mr. Pete Sharp for excellent assistance with electronics and computer software, and Mr. Mike Arends for editorial assistance. Finally, the authors wish to thank Dr. Daniel Hoyer from Novartis Pharma AG for providing us with clozapine and Dr. Jeffrey Goldstein from AstraZeneca Pharmaceuticals for providing us with quetiapine. Part of this work was presented at the International Behavioral Neuroscience Society 15th Annual Meeting in 2006.

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Amitai, N., Semenova, S. & Markou, A. Cognitive-disruptive effects of the psychotomimetic phencyclidine and attenuation by atypical antipsychotic medications in rats. Psychopharmacology 193, 521–537 (2007). https://doi.org/10.1007/s00213-007-0808-x

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