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

Br J Pharmacol. 1985 Feb;84(2):381-91. doi: 10.1111/j.1476-5381.1985.tb12922.x.


Coronal sections of rat brain (500 micron thick) were trimmed to form 'wedges' of tissue consisting of cerebral cortex and corpus callosum. 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). Responses to NMDA were reduced by magnesium ions, by the organic antagonists (-)-2-amino 5-phosphonovalerate (APV) and 2-amino 7-phosphonoheptanoate (APH), and by the dissociative anaesthetic ketamine. In this preparation, all these antagonists shifted the NMDA 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 non-competitive action, whilst Schild plots for (-)-APV, APH and ketamine appeared linear and had slopes of approximately 1. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / antagonists & inhibitors
  • Aspartic Acid / pharmacology
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / physiology
  • Corpus Callosum / drug effects
  • Corpus Callosum / physiology
  • Glutamates / pharmacology
  • Glutamic Acid
  • In Vitro Techniques
  • Kainic Acid / pharmacology
  • Ketamine / pharmacology
  • Male
  • Muscimol / pharmacology
  • N-Methylaspartate
  • Neuromuscular Depolarizing Agents*
  • Neurons / drug effects*
  • Oxadiazoles / pharmacology
  • Potassium / pharmacology
  • Quisqualic Acid
  • Rats
  • Rats, Inbred Strains
  • Tetrodotoxin / pharmacology
  • gamma-Aminobutyric Acid / pharmacology


  • Glutamates
  • Neuromuscular Depolarizing Agents
  • Oxadiazoles
  • Muscimol
  • Aspartic Acid
  • Glutamic Acid
  • Tetrodotoxin
  • gamma-Aminobutyric Acid
  • N-Methylaspartate
  • Ketamine
  • Quisqualic Acid
  • Potassium
  • Kainic Acid