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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2018-10, Vol.115 (40), p.E9479-E9488
• Main Authors: Rifkin, Robert A., Huyghe, Deborah, Li, Xiaofan, Parakala, Manasa, Aisenberg, Erin, Moss, Stephen J., Slesinger, Paul A.
• Format: Article
• Language: English
• Subjects: Addictions; Animals; Behavior disorders; Biological Sciences; Brain; Channels; Circuits; Cocaine; Cocaine - toxicity; Cocaine-Related Disorders - genetics; Cocaine-Related Disorders - metabolism; Cocaine-Related Disorders - pathology; Dopamine; Dopamine D2 receptors; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Drug abuse; G Protein-Coupled Inwardly-Rectifying Potassium Channels - genetics; G Protein-Coupled Inwardly-Rectifying Potassium Channels - metabolism; Inhibition; Locomotion - drug effects; Mice; Mice, Knockout; Narcotics; Neural networks; Neurons; Nexin; PNAS Plus; Potassium; Potassium channels; Potassium channels (inwardly-rectifying); Proteins; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D2 - metabolism; Reinforcement; Sensitivity; Sorting Nexins - genetics; Sorting Nexins - metabolism; Substantia nigra; Therapeutic applications; Ventral tegmentum; γ-Aminobutyric acid B receptors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1807788115

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.