Unusual interactions of excitatory amino acid receptor agonists: alpha- and beta-kainate antagonize motor responses to N-methyl-D-aspartate in rodents.
The alpha- and beta-stereoisomers of kainate correspond sterically to the L- and D-isomers of glutamate. Alpha-Kainate is a potent excitant at a specific membrane receptor site (kainate receptor). Beta-Kainate has been proposed as a functional N-methyl-D-aspartate antagonist in vivo. Because of the structural similarities between the alpha- and beta-stereoisomers of kainate we have investigated the interactions of both compounds with N-methyl-D-aspartate-mediated excitation in two well established animal models for assessing the action of excitatory amino acids and their antagonists in vivo: determination of CD50 (convulsant dose) for myoclonic seizures in mice and electromyographic measurement of muscle tone in genetically spastic rats. We find that alpha-kainate and beta-kainate produce myoclonic seizures in mice when given intracerebroventricularly and increase the muscle tone in genetically spastic rats when given intrathecally. Alpha-Kainate is about 5000 times more potent than beta-kainate as a convulsant and about 1000 times more active than beta-kainate in increasing the muscle tone. The excitatory actions of alpha-kainate and of beta-kainate are blocked by gamma-D-glutamylaminomethylsulphonate, a preferential kainate/quisqualate antagonist, but not by (+/-)-2-amino-7-phosphonoheptanoate, a specific N-methyl-D-aspartate antagonist. Surprisingly, alpha-kainate and beta-kainate antagonize the myoclonic seizures and the increase in muscle tone produced by N-methyl-D-aspartate, and potentiate both the anticonvulsant and myorelaxant actions of (+/-)2-amino-7-phosphonoheptanoate. Quisqualate induces myoclonic seizures in mice after intracerebroventricular application and increases muscle tone in genetically spastic rats following intrathecal injection.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D004576:Electromyography; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D009128:Muscle Spasticity / Q000235:genetics / Q000503:physiopathology; D009129:Muscle Tonus / Q000187:drug effects; D016202:N-Methylaspartate; D012640:Seizures / Q000139:chemically induced; D013237:Stereoisomerism
D001224:Aspartic Acid; D016202:N-Methylaspartate; D007608:Kainic Acid