PT - JOURNAL ARTICLE AU - V. L. Arvanov AU - R. Y. Wang TI - Clozapine, But Not Haloperidol, Prevents the Functional Hyperactivity of <em>N</em>-Methyl-<span class="sc">d</span>-Aspartate Receptors in Rat Cortical Neurons Induced by Subchronic Administration of Phencyclidine DP - 1999 May 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1000--1006 VI - 289 IP - 2 4099 - http://jpet.aspetjournals.org/content/289/2/1000.short 4100 - http://jpet.aspetjournals.org/content/289/2/1000.full SO - J Pharmacol Exp Ther1999 May 01; 289 AB - Repeated exposure of rats to the psychotomimetic drug phencyclidine (PCP) markedly increased the response of prefrontal cortical neurons to the glutamate agonist N-methyl-d-aspartate (NMDA) relative to agonist α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid. Moreover, acute challenge by PCP produced a significantly reduced block of NMDA-induced current. In addition, the subchronic administration of PCP reduced significantly the paired-pulse facilitation, accompanied by a significant increase of excitatory postsynaptic current variance. These results suggest that repeated exposure to PCP 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 responses by a PCP challenge in rats exposed repeatedly to PCP. Pretreatment with the atypical antipsychotic drug clozapine, but not the typical antipsychotic drug haloperidol, attenuates the repeated PCP-induced effect. Our results support the hypothesis that clozapine may facilitate NMDA receptor-mediated neurotransmission to improve schizophrenic-negative symptoms and cognitive dysfunction. This novel approach is useful for evaluating the cellular mechanisms of action of atypical antipsychotic drugs. The American Society for Pharmacology and Experimental Therapeutics