title: GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol.
abstract: 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.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Herman
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Harpreet
authors.initials: H
authors.lastname: Sidhu
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: David G
authors.initials: DG
authors.lastname: Stouffer
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Max
authors.initials: M
authors.lastname: Kreifeldt
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: David
authors.initials: D
authors.lastname: Le
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Chelsea
authors.initials: C
authors.lastname: Cates-Gatto
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037;
authors.forename: Michaelanne B
authors.initials: MB
authors.lastname: Munoz
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Roberts
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Loren H
authors.initials: LH
authors.lastname: Parsons
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Marisa
authors.initials: M
authors.lastname: Roberto
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455; and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wickman
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Slesinger
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037; contet@scripps.edu.
authors.forename: Candice
authors.initials: C
authors.lastname: Contet
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D063425:Binge Drinking / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D059290:Dopaminergic Neurons / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000172:deficiency / Q000378:metabolism*; D017403:In Situ Hybridization; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D009042:Motivation / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012201:Reward
chemical_list: D017931:DNA Primers; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D000431:Ethanol
keywords: Kcnj9; Kir3.3; alcohol; reward; ventral midbrain