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 beta CCE (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 beta CCE (10 mg/kg) or FG-7142 (less than or equal to 30 mg/kg) alone reversed ethanol-induced intoxication. Moreover, beta CCE (10 mg/kg), when administered just before Ro15-4513, completely antagonized the actions 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Suzdak
P D
PD
Section on Molecular Pharmacology, National Institute of Mental Health, Bethesda, Maryland.
Paul
S M
SM
Crawley
J N
JN
D000435:Alcoholic Intoxication / Q000517:prevention & control*; D000818:Animals; D001386:Azides / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects*
D001386:Azides; D002243:Carbolines; D002712:Chlorides; D007473:Ion Channels; D011720:Pyrazoles; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000431:Ethanol; C035874:FG 7142; C024915:beta-carboline-3-carboxylic acid ethyl ester; C033830:2-phenylpyrazolo(4,3-c)quinolin-3(5H)-one; C042957:Ro 15-4513