Interaction of ethanol with excitatory amino acid receptor antagonists in mice.
The purpose of the present study was to determine whether the motor impairment (myorelaxation/ataxia) induced by excitatory amino acid receptor antagonists was exaggerated by pretreatment with ethanol. The results were compared with those of gamma-aminobutyric acid(A) (GABA(A)) receptor positive modulators alone and in combination with ethanol. The excitatory amino acid receptor antagonists, dizocilpine [(+)-MK-801; (5R,1OS)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten+ ++-5,10-imine], (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), LY 326325 [(-)-(3S,4aR,6R,8R)-6-[2-(1(2)H-tetrazol-5-yl)-ethyl]-dec ahydroisoquinaline-3-carboxylic acid], LY 300164 [7,8-methylenedioxy-1-(4-aminophenyl)-4-methyl-3-acetyl-4,5-dihydro-2,3- benzodiazepine], and ACEA 1011 (5-chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione) produced dose-dependent myorelaxation/ataxia in mice as determined using the horizontal wire assay. Their behaviorally toxic doses (TD(50)s) were 0.41, 5.8, 33.0, 5.9, and 31.0 mg/kg, respectively, when administered alone i.p. In the presence of a sub-ataxic dose of ethanol (1.5 g/kg, i.p.), the TD(50)s of the excitatory amino acid antagonists were 0.13, 1.8, 10.4, 1.3, and 14.0 mg/kg, respectively. Similarly, the GABA(A) receptor positive modulators, pregnanolone, chlordiazepoxide, and pentobarbital exhibited TD(50)s of 20.8, 4.6, and 29.7 mg/kg, respectively, when administered alone and 2.7, 0.3, and 11.4 mg/kg, respectively, when administered in the presence of ethanol. Thus, similar to the GABA(A) receptor positive modulators, excitatory amino acid receptor antagonists exhibit the propensity to interact with ethanol and to have their motor side-effects exaggerated.
Vanover
K E
KE
Department of Pharmacology, CoCensys, Irvine, CA 92618, USA. kvanover@cocensys.com
D000818:Animals; D001259:Ataxia / Q000139:chemically induced; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002707:Chlordiazepoxide / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects; D010424:Pentobarbital / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D017470:Receptors, Glutamate / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology
D002492:Central Nervous System Depressants; D018691:Excitatory Amino Acid Antagonists; D006993:Hypnotics and Sedatives; D007546:Isoquinolines; D010879:Piperazines; D011810:Quinoxalines; D017470:Receptors, Glutamate; D013777:Tetrazoles; D001569:Benzodiazepines; C082999:ACEA 1011; D000431:Ethanol; D016291:Dizocilpine Maleate; D002707:Chlordiazepoxide; C082309:tezampanel; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D011280:Pregnanolone; C085266:talampanel; D010424:Pentobarbital