MODULATION OF THE SEIZURE THRESHOLD FOR EXCITATORY AMINO-ACIDS IN MICE BY ANTIEPILEPTIC DRUGS AND CHEMOCONVULSANTS

A novel method for the assessment of the threshold for clonic seizures induced by excitatory amino acids based on continuous infusion of the glutamate agonists -amino-3-hydroxy-5-tertbutyl-4-isoxazolepropionate (ATPA), kainate or N-methyl-D-aspartate (NMDA)] into the lateral brai n ventricle of unrestrained mice is reported. Using this novel method of seizure threshold determination, it was found that systemically adm inistered diphenylhydantoin and carbamazepine elevated the threshold f or ATPA and had negligible effects on the threshold for kainate and NM DA. Phenobarbital and trimethadione elevated the threshold f or all ex citatory amino acids tested, whereas valproate elevated the threshold for ATPA and kainate seizures. Ethosuximide elevated the threshold for ATPA and kainate and decreased the threshold for NMDA seizures. The q uisqualate antagonists -dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxal ine and 4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine] elevated th e threshold for ATPA and less so for kainate seizures, whereas the NMD A antagonist +/-)2-carboxypiperazine-4-yl)-propyl-1-phosphonate elevat ed the threshold for NMDA seizures. -4-methyl-7,8-methylenedioxy-5H-2, 3-benzodiazepine in higher doses was also active against NMDA seizures , whereas +/-)2-carboxypiperazine-4-yl)-propyl-1-phosphonate did so wi th kainate seizures. Among seven different convulsants, pentylenetetra zol, picrotoxin and the beta-carboline methyl 6,7-dimethoxy-4-ethyl-be ta-carboline-3-carboxylate lowered the threshold for seizures induced by excitatory amino acids. Pentylenetetrazol and picrotoxin did so wit h kainate seizures, whereas methyl 6,7-dimethoxy-4-ethyl-beta-carbolin e-3-carboxylate lowered ATPA thresholds. Bicuculline, 3-mercaptopropio nate, strychnine and pilocarpine were inactive. These data suggest tha t the method of seizure threshold determination using excitatory amino acids offers novel experimental tool allowing for better insights int o the possible mechanisms of action of antiepileptic and convulsant dr ugs.