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

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.