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Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):E9479-E9488. doi: 10.1073/pnas.1807788115. Epub 2018 Sep 18.

GIRK currents in VTA dopamine neurons control the sensitivity of mice to cocaine-induced locomotor sensitization.

Author information

1
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
2
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
3
Graduate Program in Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
4
Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
5
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02155.
6
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029; paul.slesinger@mssm.edu.

Abstract

GABABR-dependent activation of G protein-gated inwardly rectifying potassium channels (GIRK or KIR3) provides a well-known source of inhibition in the brain, but the details on how this important inhibitory pathway affects neural circuits are lacking. We used sorting nexin 27 (SNX27), an endosomal adaptor protein that associates with GIRK2c and GIRK3 subunits, to probe the role of GIRK channels in reward circuits. A conditional knockout of SNX27 in both substantia nigra pars compacta and ventral tegmental area (VTA) dopamine neurons leads to markedly smaller GABABR- and dopamine D2R-activated GIRK currents, as well as to suprasensitivity to cocaine-induced locomotor sensitization. Expression of the SNX27-insensitive GIRK2a subunit in SNX27-deficient VTA dopamine neurons restored GIRK currents and GABABR-dependent inhibition of spike firing, while also resetting the mouse's sensitivity to cocaine-dependent sensitization. These results establish a link between slow inhibition mediated by GIRK channels in VTA dopamine neurons and cocaine addiction, revealing a therapeutic target for treating addiction.

KEYWORDS:

addiction; dopamine; potassium channel; psychostimulants; ventral tegmental area

PMID:
30228121
PMCID:
PMC6176583
DOI:
10.1073/pnas.1807788115
[Indexed for MEDLINE]
Free PMC Article

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