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 development of a characteristic excitotoxic syndrome, consisting of automatisms (wet dog shakes, WDS), sustained limbic seizures and brain damage. Since kainate increases the release of excitatory amino acid neurotransmitters such as glutamate, this syndrome is thought to be due, at least in part, to excessive activation of glutamate receptors, particularly of the N-methyl-D-aspartate (NMDA) subtype. We examined the effect 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 (dizocilpine) and the GABAmimetic anticonvulsant diazepam were used. D-Cycloserine exerted a potent, dose-dependent and long-lasting anticonvulsant effect against kainate-induced seizures. At 160 mg/kg, seizures were almost completely suppressed by D-cycloserine over a 3 h observation period. No adverse effects were observed at anticonvulsant doses of D-cycloserine. In contrast to its potent effect on kainate-induced seizures, D-cycloserine did not significantly alter the number of automatisms (WDS) determined after kainate. MK-801, 0.3 mg/kg, also markedly reduced seizure severity in response to kainate, but this anticonvulsant effect was accompanied by marked motor impairment. Similarly, diazepam, 5 mg/kg, significantly attenuated kainate-induced seizures but marked ataxia was observed at this dosage. In contrast to D-cycloserine, both MK-801 and diazepam reduced WDS behaviour caused by kainate. The data demonstrate that pharmacological manipulation of the strychnine-insensitive glycine site is a powerful means of protecting against kainate-induced seizures.
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
H
H
Baran
W
W
Löscher
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M
Mevissen
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003523:Cycloserine / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007608:Kainic Acid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000819:agonists*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D013331:Strychnine / Q000494:pharmacology
D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D003523:Cycloserine; D013331:Strychnine; D003975:Diazepam; D007608:Kainic Acid