title: A Role for the GIRK3 Subunit in Methamphetamine-Induced Attenuation of GABAB Receptor-Activated GIRK Currents in VTA Dopamine Neurons.
abstract: Repeated exposure to psychostimulants induces locomotor sensitization and leads to persistent changes in the circuitry of the mesocorticolimbic dopamine (DA) system. G-protein-gated inwardly rectifying potassium (GIRK; also known as Kir3) channels mediate a slow IPSC and control the excitability of DA neurons. Repeated 5 d exposure to psychostimulants decreases the size of the GABAB receptor (GABABR)-activated GIRK currents (IBaclofen) in ventral tegmental area (VTA) DA neurons of mice, but the mechanism underlying this plasticity is poorly understood. Here, we show that methamphetamine-dependent attenuation of GABABR-GIRK currents in VTA DA neurons required activation of both D1R-like and D2R-like receptors. The methamphetamine-dependent decrease in GABABR-GIRK currents in VTA DA neurons did not depend on a mechanism of dephosphorylation of the GABAB R2 subunit found previously for other neurons in the reward pathway. Rather, the presence of the GIRK3 subunit appeared critical for the methamphetamine-dependent decrease of GABABR-GIRK current in VTA DA neurons. Together, these results highlight different regulatory mechanisms in the learning-evoked changes that occur in the VTA with repeated exposure to psychostimulants.
  
  
  CONCLUSIONS
  Exposure to addictive drugs such as psychostimulants produces persistent adaptations in inhibitory circuits within the mesolimbic dopamine system, suggesting that addictive behaviors are encoded by changes in the reward neural circuitry. One form of neuroadaptation that occurs with repeated exposure to psychostimulants is a decrease in slow inhibition, mediated by a GABAB receptor and a potassium channel. Here, we examine the subcellular mechanism that links psychostimulant exposure with changes in slow inhibition and reveal that one type of potassium channel subunit is important for mediating the effect of repeated psychostimulant exposure. Dissecting out the components of drug-dependent plasticity and uncovering novel protein targets in the reward circuit may lead to the development of new therapeutics for treating addiction.
authors.affiliation: The Salk Institute for Biological Studies, La Jolla, California 92037, Department of Biology, University of California-San Diego, La Jolla, California 92037.
authors.forename: Michaelanne B
authors.initials: MB
authors.lastname: Munoz
authors.affiliation: The Salk Institute for Biological Studies, La Jolla, California 92037.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Padgett
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Robert
authors.initials: R
authors.lastname: Rifkin
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02155, and.
authors.forename: Miho
authors.initials: M
authors.lastname: Terunuma
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wickman
authors.affiliation: The Scripps Research Institute, La Jolla, California 92037.
authors.forename: Candice
authors.initials: C
authors.lastname: Contet
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02155, and.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, The Salk Institute for Biological Studies, La Jolla, California 92037, Department of Biology, University of California-San Diego, La Jolla, California 92037, paul.slesinger@mssm.edu.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Slesinger
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001418:Baclofen / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects*; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism*; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000166:cytology*
chemical_list: D015259:Dopamine Agents; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D058786:GABA-B Receptor Agonists; D018398:Homeodomain Proteins; D018080:Receptors, GABA-B; D014157:Transcription Factors; C433629:homeobox protein PITX3; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D001418:Baclofen
keywords: PDZ; addiction; plasticity; potassium channel; psychostimulants; reward