Convulsions induced by centrally administered NMDA in mice: effects of NMDA antagonists, benzodiazepines, minor tranquilizers and anticonvulsants.
1. Convulsions were induced reproducibly by intracerebroventricular injection of N-methyl-D-aspartic acid (NMDA) to conscious mice. 2. Competitive (carboxypiperazine-propylphosphonic acid, CPP; 2-amino-7-phosphonoheptanoic acid, AP7) and non-competitive (MK801; phencyclidine, PCP; thienylcyclohexylpiperidine, TCP; dextrorphan; dextromethorphan) NMDA antagonists prevented NMDA-induced convulsions. 3. Benzodiazepine receptor agonists and partial agonists (triazolam, diazepam, clonazepam, Ro 16-6028), classical anticonvulsants (diphenylhydantoin, phenobarbitone, sodium valproate) and meprobamate were also found to prevent NMDA-induced convulsions. 4. Flumazenil (a benzodiazepine receptor antagonist) and the GABA agonists THIP and muscimol (up to subtoxic doses) were without effect. 5. Flumazenil reversed the anticonvulsant action of diazepam, but not that of MK801. 6. Results obtained in this model differ somewhat from those described in a seizure model with systemic administration of NMDA. An explanation for this discrepancy is offered. 7. This model is a simple test for assessing the in vivo activity of NMDA antagonists and also expands the battery of chemically-induced seizure models for characterizing anticonvulsants not acting at NMDA receptors.
Moreau
J L
JL
Pharmaceutical Research Department, F. Hoffmann-La Roche Ltd, Basle, Switzerland.
Pieri
L
L
Prud'hon
B
B
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology*; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001569:Benzodiazepines; D001667:Binding, Competitive / Q000187:drug effects; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D016202:N-Methylaspartate; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D001569:Benzodiazepines; D001224:Aspartic Acid; D016202:N-Methylaspartate