GABAergic compounds for the treatment of alcohol use disorder.

Decades of research have implicated the gamma-aminobutyric acid (GABA)ergic system as one of the main mediators of the behavioral effects of alcohol. Of importance, the addiction-related effects of alcohol also have been shown to be mediated in part by GABAergic systems, raising the possibility that pharmacotherapies targeting GABAergic receptors may be promising candidates for the treatment of alcohol use disorder (AUD). Alcohol modulates the activity of GAB and GAA receptors, and studies show that compounds targeting some of those receptors may decrease the addiction-related behavioral effects of alcohol. Specifically, drugs that share similar pharmacological properties with alcohol, such as positive allosteric modulators (PAMs) of GAB and GAA receptors, have been proposed as substitution therapies for AUD. Available evidence also suggests that negative allosteric modulators (NAMs) of GABAergic receptors may be potential therapeutics for AUD, although this effect is selective for specific receptor subtypes. Therefore, this Chapter reviews the available evidence on the use of GABAergic compounds for the treatment of AUD. Several GAB and GAA ligands show promising results, with a particularly positive therapeutic profile demonstrated for α5GAB receptor NAMs, α4/6δGAB receptor modulators (both positive and negative, including neurosteroids), and GAA receptor PAMs. As newer and better GABAergic compounds become available, future research should focus on understanding how these ligands can modulate different clinical symptoms of AUD, with potential new areas of research encompassing alcohol withdrawal syndrome and AUD-related insomnia.