Positive Allosteric GABA_A Receptor Modulators Reduce Ethanol Consumption and Acute Functional Tolerance

Protein kinase A (PKA) phosphorylation of GABA_A 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 GABA_A β1 subunits is not required for apremilast's effects on tolerance and drinking. Based on these findings, we hypothesized that directly activating β3-containing GABA_A receptors would produce ethanol phenotypes similar to apremilast treatment. While no known compounds selectively activate β3-containing GABA_A 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 GABA_A receptors by apremilast and direct activation by positive allosteric modulators with selectivity for β2/β3-containing receptors reduce ethanol drinking while preventing acute tolerance.