A Selective Imidazobenzodiazepine Antagonist of Ethanol in the Rat

• Published in: Science (American Association for the Advancement of Science) 1986-12, Vol.234 (4781), p.1243-1247
• Main Authors: Suzdak, Peter D., Glowa, John R., Crawley, Jacqueline N., Schwartz, Rochelle D., Skolnick, Phil, Paul, Steven M.
• Format: Article
• Language: English
• Subjects: Agonists; Alcohol; Alcoholic beverages; Alcoholism and acute alcohol poisoning; Animals; Anxiety - drug effects; Azides - pharmacology; Behavior; Benzodiazepines; Benzodiazepines - pharmacology; Biochemistry; Biological and medical sciences; Body weight; brain; chloride; Chlorides - metabolism; Dosage; Drugs; Ethanol; Ethanol - antagonists & inhibitors; Flumazenil - pharmacology; Intoxication; Male; Medical sciences; Nervous system; Physiological aspects; Pretreatment; Primates; Pyrazoles - pharmacology; Rats; Rats, Inbred Strains; Receptors; Receptors, GABA-A - drug effects; Synaptosomes - drug effects; Toxicology; vesicles
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.3022383

Ethanol, at pharmacologically relevant concentrations of 20 to 100 mM, stimulates $\gamma $-aminobutyric (GABA) receptor-mediated uptake of $^{36}$Cl-labeled chlorine into isolated brain vesicles. One drug that acts at GABA-benzodiazepine receptors, the imidazobenzodiazepine Ro 15-4513, has been found to be a potent antagonist of ethanolstimulated $^{36}$Cl$^{-}$ uptake into brain vesicles, but it fails to antagonize either pentobarbital- or muscimol-stimulated $^{36}$Cl$^{-}$ uptake. Pretreatment of rats with Ro 15-4513 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 Ro 15-4513 in antagonizing ethanol-stimulated $^{36}$Cl$^{-}$ 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 Ro 15-4513 with the GABA receptor-coupled chloride ion channel complex. The identification of a selective benzodiazepine antagonist of ethanol-stimulated $^{36}$Cl$^{-}$ 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.