Positive allosteric GABAA receptor modulators reduce ethanol consumption and acute functional tolerance.

Protein kinase A (PKA) phosphorylation of GABAA receptor β3 subunits is a mechanism by which the PDE4 inhibitor apremilast prolongs recovery from ethanol intoxication, prevents acute tolerance, and reduces drinking in mice. In contrast, PKA phosphorylation of GABAA β1 subunits is not required for apremilast's effects on tolerance and drinking. Based on these findings, we hypothesized that directly activating β3-containing GABAA receptors would produce ethanol phenotypes similar to apremilast treatment. While no known compounds selectively activate β3-containing GABAA receptors, positive allosteric modulators selective for β2/β3-over β1-subunit containing receptors do exist. We tested four such modulators (loreclezole, etifoxine, topiramate, and compound 2-261) on voluntary ethanol drinking and related behaviors in mice. Like apremilast, all four compounds dose-dependently prolonged recovery from ethanol-induced ataxia, prevented the development of acute tolerance, and reduced two-bottle choice ethanol consumption without altering blood ethanol clearance. Thus, both indirect activation of β3-containing GABAA receptors by apremilast and direct activation by positive allosteric modulators with selectivity for β2/β3-containing receptors reduce ethanol drinking while preventing acute tolerance.