Effect of glutamate receptor antagonists on N-methyl-D-aspartate- and (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced convulsant effects in mice and rats

Abstract

Selected antagonists of N-methyl-D-aspartate (NMDA) and (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, acting through different recognition sites were studied in three in vivo experimental procedures: systemic administration of NMDA or AMPA to mice and 7-day-old rats or i.c.v. injection in adult rats. Antagonists were given i.p. before the agonists. Of the substances tested (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate ((+)-MK-801, an uncompetitive NMDA receptor antagonist) and DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP-37849, a competitive NMDA receptor antagonist) were the most potent and selective NMDA receptor antagonists, having ED 50 S below 1 mg/kg in all three tests. 1-Amino-3,5-dimethyladamantane (memantine, an uncompetitive NMDA receptor antagonist) was less potent and, additionally, inhibited AMPA-induced seizures in adult rats. Aminocyclopropane carboxylic acid — a partial agonist at the glycine site coupled to NMDA receptors (Gly B) — was a weak antagonist (ED 50 > 150 mg/kg) in mice. Other partial Gly B receptor agonists, aminocyclobutane carboxylic acid, (+,R)-3-amino-1-hydroxy-2-pyrrolidone ((+,R)-HA-966) and d-cycloserine, and antagonists, 5,7-dinitroquinoxaline-2,3-dione (MNQX) and 5,7-dichlorokynurenic acid, were ineffective in mice after systemic administration. The last two agents however were active in adult rats when given i.c.v. Thus affinity, intrinsic activity (Gly B receptor partial agonists) and/or penetration into the brain (Gly B receptor antagonists) seem to be important factors in determining the effectiveness of these agents. None of the Gly B receptor antagonists or partial agonists was active in 7-day-old rats, indicating different properties of this modulatory site at this age. AMPA receptor antagonists 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline (NBQX) and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI-52466), inhibited AMPA-induced convulsions in both young (7 days) and adult rats. NBQX was 3–10 times more potent and more selective than GYKI-52466.