THE GLYCINE NMDA RECEPTOR PARTIAL AGONIST D-CYCLOSERINE BLOCKS KAINATE-INDUCED SEIZURES IN RATS - COMPARISON WITH MK-801 AND DIAZEPAM

Systemic administration of kainic acid in the rat results in the devel opment of a characteristic excitotoxic syndrome. consisting of automat isms (wet dog shakes, WDS), sustained limbic seizures and brain damage . Since kainate increases the release of excitatory amino acid neurotr ansmitters such as glutamate, this syndrome is thought to be due, at l east in part, to excessive activation of glutamate receptors, particul arly of the N-methyl-D-aspartate (NMDA) subtype. We examined the effec t of D-cycloserine, a partial agonist for the NMDA receptor-associated glycine binding site, in the kainate model of limbic seizures in rats . For comparison, the uncompetitive NMDA antagonist MK-801 (dizocilpin e) and the GABAmimetic anticonvulsant diazepam were used. D-Cycloserin e exerted a potent, dose-dependent and long-lasting anticonvulsant eff ect against kainate-induced seizures. At 160 mg/kg, seizures were almo st completely suppressed by D-cycloserine over a 3 h observation perio d. No adverse effects were observed at anticonvulsant doses of D-cyclo serine. In contrast to its potent effect on kainate-induced seizures, D-cycloserine did not significantly alter the number of automatisms (W DS) determined after kainate. MK-801, 0.3 mg/kg, also markedly reduced seizure severity in response to kainate, but this anticonvulsant effe ct was accompanied by marked motor impairment. Similarly, diazepam, 5 mg/kg, significantly attenuated kainate-induced seizures but marked at axia was observed at this dosage. In contrast to D-cycloserine, both M K-801 and diazepam reduced WDS behaviour caused by kainate. The data d emonstrate that pharmacological manipulation of the strychnine-insensi tive glycine site is a powerful means protecting against kainate-induc ed seizures.