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


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.
Amitai
Nurith
N
Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Drive, Mail Code 0603, La Jolla, CA 92093-0603, USA.
Semenova
Svetlana
S
Markou
Athina
A
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001288:Attention / Q000187:drug effects; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy*; D003987:Dibenzothiazepines / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000494:pharmacology*; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology; D007175:Impulsive Behavior; D008297:Male; D000077152:Olanzapine; D010622:Phencyclidine / Q000494:pharmacology*; D000069348:Quetiapine Fumarate; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D018967:Risperidone / Q000008:administration & dosage / Q000494:pharmacology; D012559:Schizophrenia / Q000139:chemically induced* / Q000188:drug therapy
D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D006213:Hallucinogens; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D010622:Phencyclidine; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone; D000077152:Olanzapine