Inhibitory signaling and reward: the role of GIRK channels in the mesocorticolimbic dopamine system

Abstract

Drug abuse is a critical global problem and given the current lack of efficacious pharmacotherapies to treat addiction, it is vital that we gain a better understanding of the cellular and molecular targets of drugs of abuse, and how modulation of these targets leads to addiction. Although different abused drugs work through different mechanisms of action, addiction is thought to have a common pathway, the mesocorticolimbic system, which consists of the ventral tegmental area (VTA) and reciprocal connections with downstream targets. G protein-coupled receptors (GPCRs) and downstream effectors represent a major target for drug-induced changes in mesocorticolimbic signaling. G protein-gated inwardly rectifying K+ (GIRK) channels are a key downstream target of inhibitory GPCRs and have been shown to mediate the inhibitory effects of many neurotransmitters in the CNS. Dysregulation of GPCR-GIRK signaling has been identified in a number of disorders, including addiction. This dissertation focuses on the role of GIRK-dependent inhibitory signaling throughout the mesocorticolimbic system, and how this form of signaling contributes to the cellular and reward-related behavioral effect of drugs of abuse. The importance of GIRK-dependent signaling to drug addiction is supported by the fact that several drugs of abuse can produce adaptations to the GPCR-GIRK signaling cascade. GIRK-dependent signaling was also believed to be a key regulatory of opioid effects within the mesocorticolimbic system, thought to ultimately contribute to opioid reward. Here, we challenged the opioid signaling “dogma” and show that GIRK-dependent signaling in midbrain GABA neurons is not required for disinhibition of VTA DA neurons and subsequent opioid-induced motor-stimulation. Interestingly, it appears the unique GIRK2/GIRK3 channel found in VTA DA neurons can modulate the behavioral sensitivity to opioids. In addition, we found that this GIRK2/GIRK3 channel can also modulate cocaine locomotor sensitivity, suggesting it could be a shared mechanism of other drugs of abuse. Taken together, these findings demonstrate that GPCR-GIRK inhibitory signaling in VTA DA neurons is critical to the molecular and behavioral effects of drugs of abuse. These findings also suggest that the discovery of novel compounds that modulate GIRK channel function in a subunit-dependent manner could help us prevent and/or treat addiction.