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GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol

Significance G protein-gated inwardly rectifying potassium (GIRK) channels regulate neuronal excitability and can be activated by ethanol. The role of GIRK channels in the behavioral effects of ethanol is poorly understood, however. This study shows that genetic ablation of GIRK3, one of four GIRK subunits, prevents ethanol from activating the mesolimbic dopaminergic pathway, a neuronal circuit subserving the motivation to seek reward (incentive salience), and enhances binge-like drinking. Conversely, increasing GIRK3 expression in the ventral midbrain, where this pathway originates, reduces binge-like drinking. Thus, GIRK3 appears to be a critical gatekeeper of ethanol incentive salience and a potential target for the treatment of excessive ethanol consumption. G protein-gated inwardly rectifying potassium (GIRK) channels are critical regulators of neuronal excitability and can be directly activated by ethanol. Constitutive deletion of the GIRK3 subunit has minimal phenotypic consequences, except in response to drugs of abuse. Here we investigated how the GIRK3 subunit contributes to the cellular and behavioral effects of ethanol, as well as to voluntary ethanol consumption. We found that constitutive deletion of GIRK3 in knockout (KO) mice selectively increased ethanol binge-like drinking, without affecting ethanol metabolism, sensitivity to ethanol intoxication, or continuous-access drinking. Virally mediated expression of GIRK3 in the ventral tegmental area (VTA) reversed the phenotype of GIRK3 KO mice and further decreased the intake of their wild-type counterparts. In addition, GIRK3 KO mice showed a blunted response of the mesolimbic dopaminergic (DA) pathway to ethanol, as assessed by ethanol-induced excitation of VTA neurons and DA release in the nucleus accumbens. These findings support the notion that the subunit composition of VTA GIRK channels is a critical determinant of DA neuron sensitivity to drugs of abuse. Furthermore, our study reveals the behavioral impact of this cellular effect, whereby the level of GIRK3 expression in the VTA tunes ethanol intake under binge-type conditions: the more GIRK3, the less ethanol drinking.