UC San Diego

Cognitive deficits in schizophrenia are severe and affect multiple cognitive modalities. These impairments are not adequately treated by currently available medications, and their etiology remains poorly understood. Translational animal models of cognitive deficits in schizophrenia are crucially important for the investigation of the mechanisms underlying cognitive dysfunction in schizophrenia and the development of more effective treatments for these deficits. The noncompetitive N-methyl -D-aspartate (NMDA) receptor antagonist phencyclidine (PCP) has become widely accepted as an inducing condition in models of various aspects of schizophrenia. Through exploration of a variety of doses and injection schedules, we developed a repeated PCP administration regimen that reliably induces cognitive deficits with relevance to schizophrenia. While a single injection of PCP nonspecifically suppressed responding in the 5-choice serial reaction time task (5-CSRTT), a test of multiple cognitive modalities, repeated PCP administration following our regimen selectively impaired attention, increased impulsivity, disrupted cognitive flexibility, and slowed processing speed, as assessed by the 5-CSRTT. The repeated PCP administration regimen also disinhibited impulsive responding and reduced task efficiency in the intracranial self-stimulation (ICSS) procedure, a test of reward function. Chronic treatment with clozapine, an atypical antipsychotic medication with partial effectiveness on cognitive dysfunction in schizophrenia, attenuated the attentional impairment and impulsivity induced by repeated PCP administration in the 5-CSRTT, as well as the PCP-induced disinhibition of responding in the ICSS procedure. Chronic quetiapine, another atypical antipsychotic with a different receptor profile than clozapine, and chronic nicotine did not attenuate disruptions of 5-CSRTT performance by repeated PCP administration. Acute administration of the metabotropic glutamate receptor 2/3 (mGluR2/3) agonist LY379268 exacerbated 5-CSRTT disruptions induced by repeated PCP administration. The mGluR2/3 antagonist LY341495 did not affect PCP-induced 5-CSRTT deficits when administered acutely and attenuated PCP-induced increases in 5-CSRTT timeout responding when delivered chronically. Repeated PCP administration blunted the increase in glutamate levels in the prefrontal cortex (PFC), and chronic clozapine treatment attenuated the increased PFC glutamate efflux induced by repeated PCP. In conclusion, disruptions of 5-CSRTT performance induced by repeated PCP administration constitutes a valuable model of cognitive deficits in schizophrenia that permits investigation of the neurobiological mechanisms underlying these deficits