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

Open Access
Publisher Website
Google Scholar
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.