GIRK channel activity in dopamine neurons of the ventral tegmental area bi-directionally regulates behavioral sensitivity to cocaine.

Dopamine (DA) neurons of the ventral tegmental area (VTA) have been widely implicated in the cellular and behavioral responses to drugs of abuse. Inhibitory G protein signaling mediated by GABAB receptors (GABAB Rs) and D2 DA receptors (D2 Rs) regulates the excitability of VTA DA neurons, DA neurotransmission, and behaviors modulated by DA. Most of the somatodendritic inhibitory effect of GABAB R and D2 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 employed 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 GABAB R- and D2 R-dependent signaling and increased cocaine-induced locomotor activity, while overexpression of GIRK2 increased GABAB 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. SIGNIFICANCE STATEMENT 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 bi-directionally manipulate GIRK channel activity in DA neurons of the ventral tegmental area (VTA). We found that decreasing GIRK channel activity in VTA DA neurons increased behavioral sensitivity to cocaine, while 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.