Clozapine, But Not Haloperidol, Prevents the Functional Hyperactivity of N-Methyl-d-Aspartate Receptors in Rat Cortical Neurons Induced by Subchronic Administration of Phencyclidine1

  1. V. L. Arvanov and
  2. R. Y. Wang
  1. Department of Psychiatry, State University of New York at Stony Brook, Stony Brook, New York

    Abstract

    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.

    Footnotes

    • Send reprint requests to: Rex Y. Wang, Ph.D., Department of Psychiatry and Behavioral Sciences, SUNY, Putnam Hall, South Campus, Stony Brook, NY 11794-8790. E-mail: rex.wang{at}sunysb.edu.

    • ↵1 This research was supported by U.S. Public Health Service Grant MH-41440.

    • Abbreviations:
      PCP
      phencyclidine
      ACSF
      artificial cerebrospinal fluid
      AMPA
      (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
      APD
      antipsychotic drug
      EAA
      excitatory amino acid
      EPSC
      excitatory postsynaptic current
      mcv EPSC variance = Mean2/[SD]2
      MK-801, dizocilpine
      mPFC
      medial prefrontal cortex
      NMDA
      N-methyl-d-aspartate
      PPF
      paired-pulse facilitation
      • Accepted December 23, 1998.
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    1. JPET May 1, 1999 vol. 289 no. 2 1000-1006
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