A selective imidazobenzodiazepine antagonist of ethanol in the rat.
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.
D000818:Animals; D001007:Anxiety / Q000187:drug effects; D001386:Azides / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002712:Chlorides / Q000378:metabolism; D000431:Ethanol / Q000037:antagonists & inhibitors*; D005442:Flumazenil / Q000494:pharmacology; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects
D001386:Azides; D002712:Chlorides; D011720:Pyrazoles; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000431:Ethanol; D005442:Flumazenil; C033830:2-phenylpyrazolo(4,3-c)quinolin-3(5H)-one; C042957:Ro 15-4513