Non-competitive antagonism of N-methyl-d-aspartate by displacement of an endogenous glycine-like substance.
N-methyl-D-aspartate (NMDA; 40 microM) induced depolarizations of cortical wedges that were reduced by 30 - 60% in the presence of D-2-amino-5-phosphonovalerate (D-AP5; 5 microM), ketamine (5 microM), dextrorphan (5 microM), magnesium (500 microM), kynurenate (200 microM), and 1-hydroxy-3-aminopyrrolidone-2 (HA-966; 200 microM). Superfusion with glycine (1 microM - 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 microM - 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 microM). 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 effect 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.
Fletcher
E J
EJ
Department of Basic Veterinary Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK.
Millar
J D
JD
Zeman
S
S
Lodge
D
D