GABA A Receptor Subtypes and the Abuse-Related Effects of Ethanol in Rhesus Monkeys: Experiments with Selective Positive Allosteric Modulators.

Background: Previous studies have investigated α1GABA _A and α5GABA _A receptor mechanisms in the behavioral effects of ethanol (EtOH) in monkeys. However, genetic studies in humans and preclinical studies with mutant mice suggest a role for α2GABA _A and/or α3GABA _A receptors in the effects of EtOH. The development of novel positive allosteric modulators (PAMs) with functional selectivity (i.e., selective efficacy) at α2GABA _A and α3GABA _A receptors allows for probing of these subtypes in preclinical models of the discriminative stimulus and reinforcing effects of EtOH in rhesus macaques.
Methods: In discrimination studies, subjects were trained to discriminate EtOH (2 g/kg, intragastrically) from water under a fixed-ratio (FR) schedule of food delivery. In oral self-administration studies, subjects were trained to self-administer EtOH (2% w/v) or sucrose (0.3 to 1% w/v) under an FR schedule of solution availability.
Results: In discrimination studies, functionally selective PAMs at α2GABA _A and α3GABA _A (HZ-166) or α3GABA _A (YT-III-31) receptors substituted fully (maximum percentage of EtOH-lever responding ≥80%) for the discriminative stimulus effects of EtOH without altering response rates. Full substitution for EtOH also was engendered by a nonselective PAM (triazolam), an α5GABA _A -preferring PAM (QH-ii-066) and a PAM at α2GABA _A , α3GABA _A , and α5GABA _A receptors (L-838417). A partial (MRK-696) or an α1GABA _A -preferring (zolpidem) PAM only engendered partial substitution (i.e., ~50 to 60% EtOH-lever responding). In self-administration studies, pretreatments with the functionally selective PAMs at α2GABA _A and α3GABA _A (XHe-II-053 and HZ-166) or α3GABA _A (YT-III-31 and YT-III-271) receptors increased EtOH, but not sucrose, drinking at doses that had few, or no, observable sedative-motor effects.
Conclusions: Our results confirm prior findings regarding the respective roles of α1GABA _A and α5GABA _A receptors in the discriminative stimulus effects of EtOH and, further, suggest a key facilitatory role for α3GABA _A and potentially α2GABA _A receptors in several abuse-related effects of EtOH in monkeys. Moreover, they reveal a potential role for these latter subtypes in EtOH's sedative effects.
(© 2019 by the Research Society on Alcoholism.)