Contribution of "diazepam-insensitive" GABA sub(A) receptors to the alcohol antagonist properties of Ro 15-4513 and related imidazobenzodiazepines

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 1995-01, Vol.52 (1), p.113-118
• Main Authors: Harris, B D, Moody, E J, Gu, Zi-Qiang, Skolnick, P
• Format: Article
• Language: English
• ISSN: 0091-3057

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 GABA sub(A) receptor subtype, referred to as "diazepam-insensitive" (DI). This study examined the contribution of DI GABA sub(A) 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 GABA sub(A) receptor subtype. Ro 15-4513 significantly reduced ethanol sleep time in mice. This effect was not blocked by BzR antagonists ZK 93426 and Ro 14-7437, which possess low affinities for DI but bind with high affinities to other "diazepam-sensitive" (DS) GABA sub(A) receptor isoforms. Although Ro 19-4603 also reduced ethanol sleep time, this effect was attenuated by coadministration of ZK 93426. Ro 16-6028 (2.5 mg/kg) prolonged ethanol sleep time. However, in the presence of either Ro 14-7437 or ZK 93426 ethanol-induced sleep time was reduced to values approaching those obtained with ethanol in the presence of Ro 15-4513. A low dose of ZG-63 did not significantly affect alcohol sleep time. However, in the presence of ZK 93426, ZG-63 increased sleep time. In contrast, a higher dose of ZG-63 prolonged sleep time, an effect that was attenuated by either ZK 93426 or Ro 14-7437. These findings indicate that although antagonism of ethanol-induced sleep time by Ro 15-4513 is mediated, at least in part, through DI, the contribution of this GABA sub(A) receptor isoform to the modulation of ethanol-induced sleep time by structurally related imidazobenzodiazepines is more variable. The synthesis of compounds with higher selectivity and a range of intrinsic efficacies at DI GABA sub(A) receptors is required to better define the role of this receptor isoform in ethanol-induced sleep time.