A Selective Imidazobenzodiazepine Antagonist of Ethanol in the Rat

• DOI: 10.1126/science.3022383
• Publication Date: 2006-10-05T20:28:52Z
• Authors: Peter D. Suzdak; John R. Glowa; Jacqueline N. Cra...; Rochelle D. Schwartz; Phil Skolnick; Steven M. Paul
• Keywords: Muscimol; Flumazenil; Chlordiazepoxide; Inverse agonist

Ethanol, at pharmacologically relevant concentrations of 20 to 100 mM, stimulates gamma-aminobutyric (GABA) receptor-mediated uptake 36Cl-labeled chlorine into isolated brain vesicles. One drug that acts GABA-benzodiazepine receptors, the imidazobenzodiazepine Ro15-4513, has been found be a potent antagonist ethanol-stimulated 36Cl- vesicles, but it fails antagonize either pentobarbital- or muscimol-stimulated uptake. Pretreatment rats with Ro15-4513 blocks anticonflict activity low doses ethanol (but not pentobarbital) as well behavioral intoxication observed higher ethanol. The effects in antagonizing and behavior are completely blocked by benzodiazepine receptor antagonists. However, other inverse agonists fail actions vitro vivo, suggesting novel interaction GABA receptor-coupled chloride ion channel complex. identification selective anxiolytic intoxicating suggests many neuropharmacologic may mediated via central receptors.