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

BackgroundPrevious studies have investigated 1GABA(A) and 5GABA(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 2GABA(A) and/or 3GABA(A) receptors in the effects of EtOH. The development of novel positive allosteric modulators (PAMs) with functional selectivity (i.e., selective efficacy) at 2GABA(A) and 3GABA(A) receptors allows for probing of these subtypes in preclinical models of the discriminative stimulus and reinforcing effects of EtOH in rhesus macaques. MethodsIn discrimination studies, subjects were trained to discriminate EtOH (2g/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. ResultsIn discrimination studies, functionally selective PAMs at 2GABA(A) and 3GABA(A) (HZ-166) or 3GABA(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 5GABA(A)-preferring PAM (QH-ii-066) and a PAM at 2GABA(A), 3GABA(A), and 5GABA(A) receptors (L-838417). A partial (MRK-696) or an 1GABA(A)-preferring (zolpidem) PAM only engendered partial substitution (i.e., similar to 50 to 60% EtOH-lever responding). In self-administration studies, pretreatments with the functionally selective PAMs at 2GABA(A) and 3GABA(A) (XHe-II-053 and HZ-166) or 3GABA(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. ConclusionsOur results confirm prior findings regarding the respective roles of 1GABA(A) and 5GABA(A) receptors in the discriminative stimulus effects of EtOH and, further, suggest a key facilitatory role for 3GABA(A) and potentially 2GABA(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.