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OtherNEUROPHARMACOLOGY

Clozapine and Haloperidol Modulate N-Methyl-d-aspartate- and Non-N-Methyl-d-aspartate Receptor-Mediated Neurotransmission in Rat Prefrontal Cortical Neurons In Vitro

V. L. Arvanov, X. Liang, J. Schwartz, S. Grossman and R. Y. Wang
Journal of Pharmacology and Experimental Therapeutics October 1997, 283 (1) 226-234;
V. L. Arvanov
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X. Liang
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J. Schwartz
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S. Grossman
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R. Y. Wang
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Abstract

The effects of the antipsychotic drugs haloperidol and clozapine on N-methyl-d-aspartate (NMDA) and non-NMDA receptor-mediated neurotransmission were examined and compared in pyramidal cells of the medial prefrontal cortex in rat brain slices by using the techniques of intracellular recording and single-electrode voltage-clamp. The bath administration of either haloperidol or clozapine produced a marked facilitation (300–400%) of NMDA-evoked responses in a concentration-dependent manner. The EC50 values of haloperidol and clozapine were 38 and 14 nM, respectively. At concentrations of ≥100 nM, clozapine, but not haloperidol, produced bursts of excitatory postsynaptic potentials (EPSPs), which were blocked by glutamate receptor antagonists, suggesting that these EPSPs were the result of increasing release of excitatory amino acids. Haloperidol, but not clozapine, produced a concentration-dependent inhibition of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced current with an EC50 value of 37 nM. Haloperidol significantly decreased the amplitude of EPSPs evoked by the electrical stimulation of the forceps minor, whereas clozapine increased the amplitude of these EPSPs. The study of current-voltage relationship indicates that clozapine preferentially potentiates NMDA receptor-mediated transmission, whereas haloperidol depresses the non-NMDA receptor-mediated response, which probably obscures its potentiating effect on NMDA receptor-mediated EPSPs.

Footnotes

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

  • ↵1 This work was supported by United State Public Health Service Grants MH41440 (R.Y.W.).

  • ↵2 X. Liang, V. L. Arvanov and R. Y. Wang, unpublished observations.

  • Abbreviations:
    aCSF
    artificial cerebrospinal fluid
    AMPA
    α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
    d-(−)-AP-5
    d-(−)-2-amino-5-phosphonopentanoic acid
    APD
    antipsychotic drug
    BAPTA
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
    AM
    acetoxymethyl ester
    CNQX
    6-cyano-2,3-dihydroxy-7-nitroquinoxaline
    CSF
    cerebrospinal fluid
    EAA
    excitatory amino acid
    EPSC
    excitatory postsynaptic current
    EPSP
    excitatory postsynaptic potential
    FS
    fast-spiking
    GABA
    γ-aminobutyric acid
    IB
    intrinsic bursting
    IM
    intermediate
    mPFC
    medial prefrontal cortex
    NMDA
    N-methyl-d-aspartate
    ROB
    repetitive oscillatory bursting
    RS
    regular-spiking
    TCP
    tenocyclidine
    TTX
    tetrodotoxin
    Vh
    holding potential
    • Received January 17, 1997.
    • Accepted June 2, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
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OtherNEUROPHARMACOLOGY

Clozapine and Haloperidol Modulate N-Methyl-d-aspartate- and Non-N-Methyl-d-aspartate Receptor-Mediated Neurotransmission in Rat Prefrontal Cortical Neurons In Vitro

V. L. Arvanov, X. Liang, J. Schwartz, S. Grossman and R. Y. Wang
Journal of Pharmacology and Experimental Therapeutics October 1, 1997, 283 (1) 226-234;

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OtherNEUROPHARMACOLOGY

Clozapine and Haloperidol Modulate N-Methyl-d-aspartate- and Non-N-Methyl-d-aspartate Receptor-Mediated Neurotransmission in Rat Prefrontal Cortical Neurons In Vitro

V. L. Arvanov, X. Liang, J. Schwartz, S. Grossman and R. Y. Wang
Journal of Pharmacology and Experimental Therapeutics October 1, 1997, 283 (1) 226-234;
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