Potential of GABA Receptor Positive Allosteric Modulators in the Treatment of Alcohol Use Disorder.

The orthosteric γ-aminobutyric acid (GABA) receptor agonist baclofen is currently considered a therapeutic option for alcohol use disorder (AUD); however, the safety profile of baclofen is a concern, thus arousing interest in the positive allosteric modulators (PAMs) of the GABA receptor (GABA PAMs), a new class of ligands expected to possess a better safety profile. The present paper summarizes the several lines of experimental evidence indicating the ability of GABA PAMs to inhibit multiple alcohol-motivated behaviors in rodents. All GABA PAMs tested to date have invariably been reported to reduce, or even suppress, excessive alcohol drinking, relapse- and binge-like drinking, operant oral alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced locomotor stimulation and conditioned place preference in rats and mice. The use of validated animal models of several aspects of AUD confers translational value to these findings. The reducing effects of GABA PAMs on alcohol-motivated behaviors (1) occurred at doses largely lower than those inducing sedation, suggesting that GABA PAMs may possess, if compared with baclofen, a higher therapeutic index and a more favorable safety profile, and (2) were often not associated with reductions on other non-drug consummatory behaviors. Additional findings with therapeutic potential were (1) the lack of tolerance, after repeated treatment, to the reducing effect of GABA PAMs on alcohol drinking and self-administration; (2) the efficacy of GABA PAMs after intragastric administration; and (3) the ability of GABA PAMs to selectively potentiate the suppressing effect of baclofen on alcohol self-administration. The recent transition of the first GABA PAMs to the initial steps of clinical testing makes investigation of the efficacy of GABA PAMs in AUD patients a feasible option.