Volume 84, Issue 2 p. 381-391
Free Access

Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex

Neil L. Harrison

Neil L. Harrison

MRC Neuropharmacology Research Group, Department of Pharmacology, The School of Pharmacy, 29/39 Brunswick Square, London WC1N 1AX

Laboratory of Neurophysiology, National Institute for Neurological and Communicative Disorders and Stroke, National Institutes of Health, Bldg. 36, Rm. 2C-02, Bethesda, MD 20205, U.S.A.

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Michael A. Simmonds

Corresponding Author

Michael A. Simmonds

MRC Neuropharmacology Research Group, Department of Pharmacology, The School of Pharmacy, 29/39 Brunswick Square, London WC1N 1AX

MRC Neuropharmacology Research Group, Department of Pharmacology, The School of Pharmacy, 29/39 Brunswick Square, London WC1N 1AXSearch for more papers by this author
First published: February 1985
Citations: 408

Abstract

  • 1

    Coronal sections of rat brain (500 μm thick) were trimmed to form ‘wedges’ of tissue consisting of cerebral cortex and corpus callosum.

  • 2

    When these slices were placed in a two-compartment bath, the cortical tissue could be depolarized, relative to the corpus callosum, by superfusions of high K+, or by amino acids such as l-glutamate, l-aspartate, quisqualate, kainate and N-methyl d-aspartate (NMDA).

  • 3

    Responses to NM DA were reduced by magnesium ions, by the organic antagonists (−)-2-amino 5-phosphonovalerate (APV) and 2-amino γ-phosphonoheptanoate (APH), and by the dissociative anaesthetic ketamine.

  • 4

    In this preparation, all these antagonists shifted the NM DA dose-response curve to the right in a parallel manner. A Schild plot for Mg2+ had a slope significantly less than unity, indicative of a noncompetitive action, whilst Schild plots for (−)-APV, APH and ketamine appeared linear and had slopes of approximately 1.

  • 5

    Analysis of the results of combination experiments suggested that the presumed competitive antagonists, (−)-APV and APH, share a common site of action as NMDA antagonists, and that this site is distinct from that at which ketamine exerts its action. The action of Mg2+ is clearly different from that of either (−)-APV or ketamine. It is concluded that ketamine is a non-competitive antagonist of NMDA and may act at an allosteric site on the NMDA receptor complex to influence its function.