title: GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner.
abstract: G-protein-gated inwardly rectifying K(+) (GIRK/Kir3) channel activation underlies key physiological effects of opioids, including analgesia and dependence. GIRK channel activation has also been implicated in the opioid-induced inhibition of midbrain GABA neurons and consequent disinhibition of dopamine (DA) neurons in the ventral tegmental area (VTA). Drug-induced disinhibition of VTA DA neurons has been linked to reward-related behaviors and underlies opioid-induced motor activation. Here, we demonstrate that mouse VTA GABA neurons express a GIRK channel formed by GIRK1 and GIRK2 subunits. Nevertheless, neither constitutive genetic ablation of Girk1 or Girk2, nor the selective ablation of GIRK channels in GABA neurons, diminished morphine-induced motor activity in mice. Moreover, direct activation of GIRK channels in midbrain GABA neurons did not enhance motor activity. In contrast, genetic manipulations that selectively enhanced or suppressed GIRK channel function in midbrain DA neurons correlated with decreased and increased sensitivity, respectively, to the motor-stimulatory effect of systemic morphine. Collectively, these data support the contention that the unique GIRK channel subtype in VTA DA neurons, the GIRK2/GIRK3 heteromer, regulates the sensitivity of the mouse mesolimbic DA system to drugs with addictive potential.
authors.affiliation: Department of Pharmacology and.
authors.forename: Lydia
authors.initials: L
authors.lastname: Kotecki
authors.affiliation: Department of Pharmacology and.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hearing
authors.affiliation: Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Nora M
authors.initials: NM
authors.lastname: McCall
authors.affiliation: Department of Pharmacology and.
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Marron Fernandez de Velasco
authors.affiliation: Department of Pharmacology and Minneapolis Medical Research Foundation, Minneapolis, Minnesota 55415.
authors.forename: Marco
authors.initials: M
authors.lastname: Pravetoni
authors.affiliation: Department of Pharmacology and.
authors.forename: Devinder
authors.initials: D
authors.lastname: Arora
authors.affiliation: Department of Pharmacology and.
authors.forename: Nicole C
authors.identifier: http://orcid.org/0000-0003-1641-4673
authors.initials: NC
authors.lastname: Victoria
authors.affiliation: Peptide Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, California 92037.
authors.forename: Michaelanne B
authors.initials: MB
authors.lastname: Munoz
authors.affiliation: Department of Pharmacology and.
authors.forename: Zhilian
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Peptide Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, California 92037, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Slesinger
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37235.
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.affiliation: Department of Pharmacology and Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, wickm002@umn.edu.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wickman
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology*; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D021122:Protein Subunits / Q000502:physiology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology
chemical_list: D000701:Analgesics, Opioid; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497069:Kcnj6 protein, mouse; D021122:Protein Subunits
keywords: GIRK; Kir3; conditional knockout; morphine; rostromedial tegmental area; ventral tegmental area