PubMed · 7062946
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1982-03-25. Drugs to decrease alcohol consumption.. https://doi.org/10.1056/nejm198203253061217
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In a situation offering a free choice between 0.1% saccharin solution and tap water, Fawn Hooded (FH) rats consumed 363.0 +/- 33.5 ml/kg/day of saccharin solution. Subsequently those animals drank 3.0 +/- 0.4 g/kg of ethanol in a free choice between water and 10% ethanol solution. Control FH rats that did not have access to saccharin consumed 5.0 +/- 0.5 between groups was significant: p = 0.006). When control rats were exposed to the choice between 10% ethanol solution and 0.1% saccharin solution for 4 days they consumed 383.7 +/- 27.5 ml/kg/day of saccharin solution and their ethanol intake dropped to 1.2 +/- 0.3 g/kg/day. When these rats were returned back to alcohol/water choice and exposure to saccharin was discontinued, their alcohol intake was still reduced (3.7 +/- 0.3 g/kg/day for at least 10 consecutive days). Exposure of alcohol-experienced alcohol-preferring P rats with high (6.8 +/- 0.5 g/kg/day) and stable alcohol intake to saccharin/water choice for 4 days also resulted in a significant attenuation of their ethanol intake for at least 6 days following saccharin cessation. Thus, voluntary consumption of saccharin can suppress subsequent alcohol intake in both alcohol-naive and alcohol-experienced rats.
Both in vivo and in vitro studies have shown that Ro 15-4513 can antagonize many of the pharmacologic actions of ethanol. In contrast to many benzodiazepine receptor (BzR) ligands, Ro 15-4513 binds with high affinity to a novel GABAA receptor subtype, referred to as "diazepam-insensitive" (DI). This study examined the contribution of DI GABAA receptors to the modulation of ethanol-induced sleep time by Ro 15-4513 and related imidazobenzodiazepines [e.g., Ro 19-4603, Ro 16-6028, and ZG-63 (t-butyl-8-chloro-5,6-dihydro-5-methyl-6-oxo-imidazo[1,5,a] [1,4]benzodiazepine-3-carboxylate)] that possess high affinities for this GABAA receptor subtype. Ro 15-4513 (0.6-5 mg/kg) significantly reduced ethanol (3.5 g/kg, i.p.) sleep time in mice (p < 0.001, analysis of variance). This effect was not blocked by BzR antagonists ZK 93426 (5 mg/kg) and Ro 14-7437 (5 mg/kg), which possess low affinities for DI but bind with high affinities to other "diazepam-sensitive" (DS) GABAA receptor isoforms. Although Ro 19-4603 (2.5 mg/kg) also reduced ethanol sleep time (p < 0.01), this effect was attenuated by coadministration of ZK 93426 (2.5 mg/kg). Ro 16-6028 (2.5 mg/kg) prolonged (p < 0.01) ethanol sleep time. However, in the presence of either Ro 19-7437 (5 mg/kg) or ZK 93426 (2.5 mg/kg) ethanol-induced sleep time was reduced to values approaching those obtained with ethanol in the presence of Ro 15-4513. A low dose (2.5 mg/kg) of ZG-63 did not significantly affect alcohol sleep time. However, in the presence of ZK 93426, ZG-63 increased sleep time (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)