EFFECT OF GLUTAMATE-RECEPTOR ANTAGONISTS ON N-METHYL-D-ASPARTATE ACID AND (S)-ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONIC ACID-INDUCED CONVULSANT EFFECTS IN MICE AND RATS

Selected antagonists of N-methyl-D-aspartate (NMDA) and (S)-alpha-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, MK-801, an uncompetitive NMDA receptor antagonist) and DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP-7849, 37849, a competitive NMDA receptor antagonist) were the most potent and selective NMDA receptor antagonists, having ED50s 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,) - was a weak antagonist (ED50 > 150 mg/kg) in mice. Other partial Gly, 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, 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.