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

Abstract

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.

Keywords: Alpha; Drug Discrimination; Ethanol; GABAA; Self-Administration.