Article date: 1986/12/5
PubMed ID: 3022383
Journal name: Science (New York, N.Y.) (ISSN: 0036-8075)
Ethanol, at pharmacologically relevant concentrations of 20 to 100 mM, stimulates gamma-aminobutyric (GABA) receptor-mediated uptake of 36Cl-labeled chlorine into isolated brain vesicles. One drug that acts at GABA-benzodiazepine receptors, the imidazobenzodiazepine Ro15-4513, has been found to be a potent antagonist of ethanol-stimulated 36Cl- uptake into brain vesicles, but it fails to antagonize either pentobarbital- or muscimol-stimulated 36Cl- uptake. Pretreatment of rats with Ro15-4513 blocks the anticonflict activity of low doses of ethanol (but not pentobarbital) as well as the behavioral intoxication observed with higher doses of ethanol. The effects of Ro15-4513 in antagonizing ethanol-stimulated 36Cl- uptake and behavior are completely blocked by benzodiazepine receptor antagonists. However, other benzodiazepine receptor inverse agonists fail to antagonize the actions of ethanol in vitro or in vivo, suggesting a novel interaction of Ro15-4513 with the GABA receptor-coupled chloride ion channel complex. The identification of a selective benzodiazepine antagonist of ethanol-stimulated 36Cl- uptake in vitro that blocks the anxiolytic and intoxicating actions of ethanol suggests that many of the neuropharmacologic actions of ethanol may be mediated via central GABA receptors.
Author List: Suzdak P D, Glowa J R, Crawley J N, Schwartz R D, Skolnick P, Paul S M
Publication Types: Journal Article
Substances mentioned in the article: Azides; Chlorides; Pyrazoles; Receptors, GABA-A; Benzodiazepines; Ethanol; Flumazenil; 2-phenylpyrazolo(4,3-c)quinolin-3(5H)-one; Ro 15-4513;
Mesh terms: Animals; Anxiety/drug effects; Azides/pharmacology; Benzodiazepines/pharmacology; Chlorides/metabolism; Ethanol/antagonists & inhibitors; Flumazenil/pharmacology; Male; Pyrazoles/pharmacology; Rats; Rats, Inbred Strains; Receptors, GABA-A/drug effects; Synaptosomes/drug effects;