Contribution of "diazepam-insensitive" GABAA receptors to the alcohol antagonist properties of Ro 15-4513 and related imidazobenzodiazepines.
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)
Harris
B D
BD
Laboratory of Neuroscience, NIDDK, National Institutes of Health, Bethesda, MD 20892-0008, USA.
Moody
E J
EJ
Gu
Z Q
ZQ
Skolnick
P
P
D000427:Alcohol Deterrents / Q000494:pharmacology*; D000818:Animals; D001386:Azides / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains
D000427:Alcohol Deterrents; D001386:Azides; D002243:Carbolines; D018756:GABA Antagonists; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D001569:Benzodiazepines; C038674:Ro 14-7437; C042568:ZK 93426; C042957:Ro 15-4513; D003975:Diazepam