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Research ArticleArticle

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

V. L. Arvanov and R. Y. Wang
Journal of Pharmacology and Experimental Therapeutics May 1999, 289 (2) 1000-1006;
V. L. Arvanov
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R. Y. Wang
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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.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 289 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 289, Issue 2
1 May 1999
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Research ArticleArticle

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

V. L. Arvanov and R. Y. Wang
Journal of Pharmacology and Experimental Therapeutics May 1, 1999, 289 (2) 1000-1006;

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Research ArticleArticle

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

V. L. Arvanov and R. Y. Wang
Journal of Pharmacology and Experimental Therapeutics May 1, 1999, 289 (2) 1000-1006;
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