The Modulatory Role for Galanin Signaling in the VTA in Opioid Reward

Abstract ID 102826 Poster Board 314 The opioid epidemic is a national public health crisis, with opioid overdoses accounting for more than 75% of all drug-related overdose deaths in the United States. In addition to the alarming overdose rates, more than three million Americans suffer from opioid use disorder (OUD). Not only are the effects of OUD devastating for individuals and families affected, but this epidemic also poses a significant economic burden on society. The cost of OUD in the United States was estimated at nearly $1.5 trillion in 2020, and these costs are expected to increase as a consequence of the pandemic among other factors. Despite this national emergency, there are only three FDA-approved medications for the treatment of OUD, and each of these have side effects including respiratory depression, diversion for illicit use, and a necessary detoxification period. Therefore, it is critical that we identify novel pharmacotherapies for OUD. One approach to developing new treatments involves targeting endogenous neurobiological circuits that modulate opioid addiction-related behaviors. Opioid reward is mediated, in part, by suppressing GABA transmission in the ventral tegmental area (VTA) via μ opioid receptor (MOR) activation, thus disinhibiting local dopamine (DA) neurons. Importantly, galanin is an endogenous neuropeptide that regulates opioid responses, most notably opposing opioid reward. Prior studies have demonstrated that mice lacking galanin globally exhibit increased morphine-induced locomotor activity and conditioned place preference (CPP), whereas ICV infusion of galanin has the opposite effect and suppresses morphine CPP. Importantly, galanin receptor 1 (GalR1) is co-expressed with MOR in a subset of GABA neurons that innervate the VTA, and galanin signaling via MOR-GalR1 heteromers suppresses MOR-induced increases in extracellular DA. Therefore, galanin transmission in the VTA may represent a therapeutic target for OUD, but the neurocircuitry and molecular mechanisms underlying the ability of galanin to oppose opioid reward remain unknown. The current experiments were designed to determine 1) the endogenous source of galanin in the VTA, and 2) the impact of galanin signaling in the VTA on morphine CPP. To determine the endogenous source of galanin to the VTA, adult, male and female Wild Type (C57BL/6) mice were infused with a retro-GFP virus into the VTA, and brain-wide RNAscope was used to identify cells containing both GFP and galanin mRNA. Furthermore, to determine the role for VTA galanin in morphine CPP, male and female mice were implanted with indwelling bilateral cannulae in the VTA and received galanin (400 ng/side) 20 min prior to morphine CPP training. We found that intra-VTA galanin infusion attenuated morphine CPP. We are currently examining the specific role of the MOR-GalR1 heteromer via co-administration of galanin and a heteromer interfering peptide into the VTA during morphine CPP. Together, these findings suggest that galanin signaling the VTA represents a viable target for modulating opioid reward. Furthermore, these behavioral studies lay the foundation for investigating galanin signaling within the VTA as novel therapeutic target for OUD. This work was supported by the National Institute of Drug Abuse extramural program (R01DA038453 and R01DA049257).