GABA_A Receptor Subtypes and the Abuse-Related Effects of Ethanol in Rhesus Monkeys: Experiments with Selective...

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.

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.

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.

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.