LY-300164, A NOVEL ANTAGONIST OF AMPA KAINATE RECEPTORS, POTENTIATES THE ANTICONVULSIVE ACTIVITY OF ANTIEPILEPTIC DRUGS/

LY 300164 inophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo(4,5 H)-2,3-be nzodiazepine]: administered intraperitoneally up to 2 mg/kg, did not i nfluence the threshold for electroconvulsions. In doses of 2.5-4 mg/kg , LY 300164 significantly raised the threshold. In subprotective doses against electroconvulsions, this excitatory amino acid receptor antag onist enhanced the protective activity of intraperitoneally given valp roate, carbamazepine and diphenylhydantoin against maximal electroshoc k-induced convulsions in mice. The anticonvulsive action of phenobarbi tal was potentiated by LY 300164 only at 2 mg/kg. The non-N-methyl-D-a spartate receptor antagonist did not affect the plasma levels of the a ntiepileptic drugs, so a pharmacokinetic interaction is not probable. Combined treatment with LY 300164 (2 mg/kg) and the antiepileptics stu died (providing 50% protection against maximal electroshock) did not i mpair the motor performance of mice, evaluated in the chimney test. Va lproate, at its ED50 of 280 mg/kg against maximal electroshock, produc ed meter impairment. As shown in the passive avoidance task, combinati on of LY 300164 (2 mg/kg) with valproate or diphenylhydantoin resulted in impairment of long-term memory. Alone among the antiepileptics, va lproate (280 mg/kg) and phenobarbital (28.5 mg/kg) disturbed long-term memory. The results suggest that blockade of glutamate-mediated event s via non-NMDA receptors leads to enhancement of the anticonvulsive ac tivity of conventional antiepileptics. Some combinations of LY 300164 with antiepileptic drugs were superior to these antiepileptics alone i n terms of their lack of adverse effects. (C) 1998 Elsevier Science B. V. All rights reserved.