GIRK Channel Activity in Dopamine Neurons of the Ventral Tegmental Area Bidirectionally Regulates Behavioral Sensitivity to Cocaine

• Published in: The Journal of neuroscience 2019-05, Vol.39 (19), p.3600-3610
• Main Authors: McCall, Nora M, Marron Fernandez de Velasco, Ezequiel, Wickman, Kevin
• Format: Article
• Language: English
• Subjects: Activation; Anxiety; Behavior; Channel gating; Cocaine; Dopamine; Dopamine D2 receptors; Dopamine receptors; Drug abuse; Drug development; Excitability; Locomotion; Locomotor activity; Mental depression; Mice; Narcotics; Neurons; Neurotransmission; Potassium channels (inwardly-rectifying); Proteins; Receptors; Sensitivity; Signaling; Therapeutic applications; Ventral tegmentum; γ-Aminobutyric acid B receptors
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.3101-18.2019

Dopamine (DA) neurons of the VTA have been widely implicated in the cellular and behavioral responses to drugs of abuse. Inhibitory G protein signaling mediated by GABA receptors (GABA Rs) and D DA receptors (D Rs) regulates the excitability of VTA DA neurons, DA neurotransmission, and behaviors modulated by DA. Most of the somatodendritic inhibitory effect of GABA R and D R activation on DA neurons reflects the activation of G protein-gated inwardly rectifying K (GIRK) channels. Furthermore, GIRK-dependent signaling in VTA DA neurons can be weakened by exposure to psychostimulants and strengthened by phasic DA neuron firing. The objective of this study was to determine how the strength of GIRK channel activity in VTA DA neurons influences sensitivity to cocaine. We used a Cre-dependent viral strategy to overexpress the individual GIRK channel subunits in VTA DA neurons of male and female adult mice, leading to enhancement (GIRK2) or suppression (GIRK3) of GIRK channel activity. Overexpression of GIRK3 decreased somatodendritic GABA R- and D R-dependent signaling and increased cocaine-induced locomotor activity, whereas overexpression of GIRK2 increased GABA R-dependent signaling and decreased cocaine-induced locomotion. Neither manipulation impacted anxiety- or depression-related behavior, despite the link between such behaviors and DA signaling. Together, these data show that behavioral sensitivity to cocaine in mice is inversely proportional to the strength of GIRK channel activity in VTA DA neurons and suggest that direct activators of the unique VTA DA neuron GIRK channel subtype (GIRK2/GIRK3 heteromer) could represent a promising therapeutic target for treatment of addiction. Inhibitory G protein signaling in dopamine (DA) neurons, including that mediated by G protein-gated inwardly rectifying K (GIRK) channels, has been implicated in behavioral sensitivity to cocaine. Here, we used a viral approach to bidirectionally manipulate GIRK channel activity in DA neurons of the VTA. We found that decreasing GIRK channel activity in VTA DA neurons increased behavioral sensitivity to cocaine, whereas increasing GIRK channel activity decreased behavioral sensitivity to cocaine. These manipulations did not alter anxiety- or depression-related behaviors. These data highlight the unique GIRK channel subtype in VTA DA neurons as a possible therapeutic target for addiction.