A selective imidazobenzodiazepine antagonist of ethanol in the rat

Peter D. Suzdak, John R. Glowa, Jacqueline N. Crawley, Rochelle D. Schwartz, Phil Skolnick, Steven M. Paul

Research output: Contribution to journalArticlepeer-review

501 Scopus citations


Ethanol, at pharmacologically relevant concentrations of 20 to 100 mM, stimulates γ-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.

Original languageEnglish
Pages (from-to)1243-1247
Number of pages5
Issue number4781
StatePublished - 1986


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