Non-Competitive Antagonism of N-Methyl-D-Aspartate by Displacement of an Endogenous Glycine-Like Substance
Article first published online: 7 APR 2006
European Journal of Neuroscience
Volume 1, Issue 3, pages 196–203, May 1989
How to Cite
Fletcher, E. J., Millar, J. D., Zeman, S. and Lodge, D. (1989), Non-Competitive Antagonism of N-Methyl-D-Aspartate by Displacement of an Endogenous Glycine-Like Substance. European Journal of Neuroscience, 1: 196–203. doi: 10.1111/j.1460-9568.1989.tb00788.x
- Issue published online: 7 APR 2006
- Article first published online: 7 APR 2006
- Received 3 October 1988; revised 16 January 1989, accepted 16 January 1989
- glutamate receptors;
- kynurenic acid;
N-methyl-D-aspartate (NMDA; 40 μM) induced depolarizations of cortical wedges that were reduced by 30–60% in the presence of D-2-amino-5-phosphonovalerate (D-AP5; 5 μM), ketamine (5 μM), dextrorphan (5 μM), magnesium (500 μM), kynurenate (200 μM), and 1-hydroxy-3-aminopyrrolidone-2 (HA-966; 200 μM). Superfusion with glycine (1 μM-1 mM) did not enhance the action of NMDA in control medium and in media containing D-AP5, ketamine, dextrorphan, or magnesium. In the presence of kynurenate and HA-966, however, NMDA-induced depolarizations were enhanced in a dose-dependent manner by glycine (10 μM-3.16 mM). NMDA antagonism produced by HA-966 appeared to be more completely reversed than that produced by kynurenate. This action of glycine was mimicked by D-serine but not by GABA or L-serine, and was resistant to strychnine (10–50 μM). Reduction of responses to quisqualate by kynurenate was not reversed by glycine.
In these cortical wedges, spontaneous synaptic activity was observed in nominally magnesium-free medium and this epileptiform activity could be blocked by the above NMDA antagonists. Glycine and D-serine reversed only the effects of kynurenate and HA-966 on such synaptic activity.
These results suggest there is an endogenous glycine-like compound acting on NMDA receptor-ionophore complexes and that displacement of this compound by HA-966 or kynurenate produces antagonism of NMDA.