Dissociation of acute and chronic intermittent phencyclidine-induced performance deficits in the 5-choice serial reaction time task: influence of clozapine.

Cognitive problems in schizophrenia are not well treated by current drugs. The drug PCP is often used in animals to model these problems. In rats, a single dose of PCP increased impulsive, anticipatory responses 30 minutes after injection, but this effect disappeared within 24 hours. Repeated PCP treatment caused lasting delays in cognitive processing speed, which were partly improved by the antipsychotic clozapine. Clozapine also modified a measure of risk-taking versus caution (lnBeta) that was persistently altered by repeated PCP. The findings suggest that repeated PCP treatment combined with signal detection analysis provides a useful method for testing new cognitive enhancers.

Study at a glance

Abstract

Cognitive deficits are a core feature of schizophrenia that respond minimally to existing drugs. PCP is commonly used to model schizophrenia-like deficits preclinically although different dosing protocols may affect different domains. Here we characterise the acute, and chronic intermittent effects of PCP in the 5-choice serial reaction time task (5-CSRTT) in rats, and assess the effects of clozapine. In a novel approach, we also assess the effects of increased inhibitory load and conduct clinically relevant signal detection analysis (SDA). The effects of acute and repeated PCP (2.58 mg/kg) treatment on attentional processes and inhibitory control were assessed during and following the chronic treatment regime in the presence or absence of chronic clozapine (20 mg/kg/day). Thirty minutes post-PCP injection, there was an increase in anticipatory responding which disappeared after 24 h. Although, acute PCP did not change accuracy of responding or processing speed, repeated PCP revealed delayed deficits in cognitive processing speed which were partly ameliorated by clozapine. Extended inter-trial intervals increased premature responding, while SDA revealed that clozapine modified persistent PCP-induced deficits in lnBeta (a composite measure of risk taking versus caution). Acute NMDA receptor antagonism impairs inhibitory control, whereas repeated treatment produces delayed deficits in cognitive processing speed. The ability of clozapine partially to restore persistent PCP-induced deficits in processing speed and in lnBeta is consistent with clinical findings. This suggests that the enduring effects of repeated PCP treatment, combined with SDA, offers a useful, translational, approach to evaluate novel cognitive enhancers in the 5-CSRTT.