Modulation of seizure susceptibility in the mouse by the strychnine-insensitive glycine recognition site of the NMDA receptor/ion channel complex.
1. In order to determine whether the strychnine-insensitive glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor/ion channel complex is fully activated in vivo, the ability of the selective glycine receptor agonist, D-serine, to modulate seizure susceptibility in the mouse has been examined. 2. D-Serine (10-200 micrograms per mouse, i.c.v.) dose-dependently increased the potency of NMDLA in inducing seizures in Swiss Webster mice by approximately 3 fold. L-Serine was without significant effect. 3. The potency of pentylenetetrazol in inducing seizures was also enhanced by D-, but not L-serine, although the magnitude of the shift (1.6 fold) was considerably less than for NMDLA. 4. Similar doses of D-serine were also able to block the anticonvulsant effect of the non-selective glycine receptor antagonist, kynurenic acid, against seizures induced by NMDLA, but were without effect on the anticonvulsant effect of the competitive NMDA receptor antagonist, 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). 5. D-Serine completely antagonized the protective effect of the selective glycine receptor antagonist, 7-chlorokynurenic acid, against sound-induced seizures in DBA/2 mice, but was less effective in this model against the less selective antagonist, kynurenic acid. 6 The results indicate that in vivo, NMDA receptors are not maximally potentiated by endogenous glycine and suggest an important involvement of the glycine modulatory site on the NMDA receptor/ion channel complex in the pathophysiology of epilepsy.
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex.
L
L
Singh
R J
RJ
Oles
M D
MD
Tricklebank
D000161:Acoustic Stimulation; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives; D003975:Diazepam / Q000494:pharmacology; D007276:Injections, Intraventricular; D007473:Ion Channels / Q000187:drug effects*; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016202:N-Methylaspartate; D010433:Pentylenetetrazole; D010879:Piperazines; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D012694:Serine; D013331:Strychnine / Q000494:pharmacology
D007473:Ion Channels; D010879:Piperazines; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D001224:Aspartic Acid; D012694:Serine; D016202:N-Methylaspartate; D007736:Kynurenic Acid; D013331:Strychnine; D003975:Diazepam; C015068:1-(3-chlorophenyl)piperazine; C057013:7-chlorokynurenic acid; D010433:Pentylenetetrazole