Modulation of the seizure threshold for excitatory amino acids in mice by antiepileptic drugs and chemoconvulsants

KG Steppuhn and L Turski

Research Laboratories of Schering AG, Berlin, Germany.

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 [alpha-amino-3-hydroxy-5-terbutyl-4- isoxazolepropionate (ATPA), kainate or N-methyl-D-aspartate (NMDA)] into the lateral brain ventricle of unrestrained mice is reported. Using this novel method of seizure threshold determination, it was found that systemically administered diphenylhydantoin and carbamazepine elevated the threshold for ATPA and had negligible effects on the threshold for kainate and NMDA. Phenobarbital and trimethadione elevated the threshold for all excitatory 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 quisqualate antagonists [2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline and 1-(4- aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine] elevated the threshold for ATPA and less so for kainate seizures, whereas the NMDA antagonist 3-((+-)2-carboxypiperazine-4-yl)-propyl-1- phosphonate elevated the threshold for NMDA seizures. 1-(4- Aminophenyl)4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in higher doses was also active against NMDA seizures, whereas 3-((+-)2- carboxypiperazine-4-yl)-propyl-1-phosphonate did so with kainate seizures. Among seven different convulsants, pentylenetetrazol, picrotoxin and the beta-carboline methyl 6,7-dimethoxy-4-ethyl-beta- carboline-3-carboxylate lowered the threshold for seizures induced by excitatory amino acids. Pentylenetetrazol and picrotoxin did so with kainate seizures, whereas methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3- carboxylate lowered ATPA thresholds. Bicuculline, 3-mercaptopropionate, strychnine and pilocarpine were inactive.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 265, Issue 3, pp. 1063-1070, 06/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

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