Effect of glutamate receptor antagonists on N-methyl-D-aspartate- 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, 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 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 (GlyB)--was a weak antagonist (ED50 > 150 mg/kg) in mice. Other partial GlyB receptor agonists, aminocyclobutane carboxylic acid, (+,R)-3-amino-1-hydroxy-2-pyrrolidine ((+,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 (GlyB receptor partial agonists) and/or penetration into the brain (GlyB receptor antagonists) seem to be important factors in determining the effectiveness of these agents.(ABSTRACT TRUNCATED AT 250 WORDS)
Bisaga
A
A
Department of Pharmacology, Institute of Psychiatry and Neurology, Warsaw, Poland.
Krzascik
P
P
Jankowska
E
E
Palejko
W
W
Kostowski
W
W
Danysz
W
W
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists; D005260:Female; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000037:antagonists & inhibitors*
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid