GIRK channels modulate opioid-induced motor activity in a cell type- and subunit-dependent manner

Lydia Kotecki, Matthew Hearing, Nora M. McCall, Ezequiel Marron Fernandez de Velasco, Marco Pravetoni, Devinder Arora, Nicole C. Victoria, Michaelanne B. Munoz, Zhilian Xia, Paul A. Slesinger, C. David Weaver, Kevin Wickman

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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 orGirk2, 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.

Original languageEnglish (US)
Pages (from-to)7131-7142
Number of pages12
JournalJournal of Neuroscience
Volume35
Issue number18
DOIs
StatePublished - May 6 2015

Keywords

  • Conditional knockout
  • GIRK
  • Kir3
  • Morphine
  • Rostromedial tegmental area
  • Ventral tegmental area

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