Clozapine, but not haloperidol, prevents the functional hyperactivity of N-methyl-D-aspartate receptors in rat cortical neurons induced by subchronicadministration of phencyclidine

Repeated exposure of rats to the psychotomimetic drug phencyclidine (PCP) m arkedly increased the response of prefrontal cortical neurons to the glutam ate agonist N-methyl-D-aspartate (NMDA) relative to agonist alpha-amino-3-h ydroxy-5-methylisoxazole-4-propionic acid. Moreover, acute challenge by PCP produced a significantly reduced block of NMDA-induced current. In additio n, the subchronic administration of PCP reduced significantly the paired-pu lse facilitation, accompanied by a significant increase of excitatory posts ynaptic current variance. These results suggest that repeated exposure to P CP increased evoked release of excitatory amino acids. The enhanced release of excitatory amino acids evoked by NMDA could explain, at least partly, a hypersensitive response to NMDA and a reduced blockade of the NMDA respons es by a PCP challenge in rats exposed repeatedly to PCP. Pretreatment with the atypical antipsychotic drug clozapine, but not the typical antipsychoti c drug haloperidol, attenuates the repeated PCP-induced effect. Our results support the hypothesis that clozapine may facilitate NMDA receptor-mediate d neurotransmission to improve schizophrenic-negative symptoms and cognitiv e dysfunction. This novel approach is useful for evaluating the cellular me chanisms of action of atypical antipsychotic drugs.