Effects of Ro15-4513 and other benzodiazepine receptor inverse agonists on alcohol-induced intoxication in the rat

The ability of the imidazobenzodiazepine Ro15-4513 to antagonize the behavioral intoxication produced by ethanol and related short-chain alcohols was examined in the rat. Ro15-4513 dose dependently (0.5-10 mg/kg i.p.: IC₅₀, 1.5 mg/kg) inhibited the intoxication induced by ethanol (2 g/kg), as well as t-amyl alcohol (0.36 g/kg) and methanol (4.66 g/kg). The effects of Ro15-4513 in blocking ethanol-induced intoxication were blocked by the benzodiazepine receptor antagonists Ro15-1788 and CGS-8216. However, Ro15-4513 was ineffective in antagonizing the intoxication observed after higher doses of ethanol (4 g/kg). In contrast, ethanol-induced intoxication was not antagonized by the benzodiazepine receptor antagonists Ro15-1788 (10 mg/kg) or CGS-8216 (20 mg/kg), nor by the inverse agonists FG-7142 (10-30 mg/kg) or βCCE (10 mg/kg). When administered after ethanol, Ro15-4513 also reversed ethanol-induced intoxication in a dose-dependent manner (2.5-10 mg/kg i.p.: IC₅₀, 5 mg/kg), an effect which was also blocked by Ro15-1788 and CGS-8216. However, neither βCCE (10 mg/kg) or FG-7142 (≤30 mg/kg) alone reversed ethanol-induced intoxication. Moreover, βCCE (10 mg/kg), when administered just before Ro15-4513, completely antagonized the action of Ro15-4513 in reversing ethanol-induced intoxication. These data suggest that the ability of Ro15-4513 to antagonize, and to reverse, ethanol-induced intoxication is mediated via central benzodiazepine receptors. However, the lack of effect of other benzodiazepine receptor-inverse agonists administered at comparable or even greater doses suggests that the 'alcohol blocking' properties of Ro15-4513 are mediated through some unique interaction with the γ-aminobutyric acid/benzodiazepine receptor-coupled Cl^- ion channel. It may therefore be possible to dissociate the alcohol-antagonizing properties of Ro15-4513 from its inverse agonist properties.