Selective blockade of N-methyl-D-aspartate (NMDA)-induced convulsions by NMDA antagonists and putative glycine antagonists: relationship with phencyclidine-like behavioral effects.
Antagonism of N-methyl-D-aspartate (NMDA)-induced convulsions by a variety of drugs was compared with their ability to produce phencyclidine (PCP)-like behavioral effects (locomotion and falling) in mice. Convulsions produced by i.c.v. administration of NMDA were antagonized, at doses that did not block kainate- and quisqualate-induced convulsions, by competitive NMDA antagonists (e.g., CPP and CGS 19755), noncompetitive antagonists (e.g., PCP and MK-801) and also by some putative glycine antagonists (7-chlorokynurenic acid and HA-966). Only the competitive and the noncompetitive NMDA antagonists produced locomotion and falling, and their potencies to do so correlated (r = 0.92) with their relative potencies to antagonize NMDA-induced convulsions. However, the PCP-like behavioral effects produced by the competitive antagonists were of a lesser magnitude than those of the noncompetitive antagonists, and occurred at doses higher than those needed to block NMDA-induced convulsions. The putative glycine antagonists 7-chlorokynurenic acid and HA-966 selectively blocked NMDA-induced convulsions, without producing PCP-like behavioral effects. The extent to which compounds produce PCP-like behavioral effects might depend in part on the specific component of the NMDA receptor complex with which they interact: i.e., the NMDA receptor, the NMDA receptor-associated ion channel or the glycine-sensitive modulatory site.
Koek
W
W
Neurobiology Division, FONDAX, Groupe de Recherche SERVIER, Puteaux, France.
Colpaert
F C
FC
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000037:antagonists & inhibitors*; D007608:Kainic Acid / Q000494:pharmacology; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D016202:N-Methylaspartate; D010069:Oxadiazoles / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology; D016318:Quisqualic Acid; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control
D010069:Oxadiazoles; D011760:Pyrrolidinones; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D001224:Aspartic Acid; D016202:N-Methylaspartate; D016318:Quisqualic Acid; C001369:1-hydroxy-3-amino-2-pyrrolidone; D007736:Kynurenic Acid; D010622:Phencyclidine; C057013:7-chlorokynurenic acid; D007608:Kainic Acid; D005998:Glycine