Examining the modulatory role of galanin in opioid reward

Emory University, Atlanta GA

Investigators

Abstract

PROJECT SUMMARY The opioid epidemic in the United States has reached critical proportions, with opioid-related overdoses contributing to more than 75% of drug overdose deaths. This crisis not only leads to significant mortality rates but also poses a significant economic burden on society. Despite the prevalence of opioid use disorders (OUD), the available treatment options remain limited, with only 3 FDA-approved medications, and there is a critical need to develop novel therapeutics. One way to develop novel treatments is by examining endogenous factors that modulate opioid responses such as galanin, a neuropeptide that is known to oppose opioid reward. Galanin signals through three G-protein coupled receptors (GPCRs) including GalR1, which preferentially forms heteromers with µ-opioid receptors (MOR) in the ventral tegmental area (VTA), a key node in the mesolimbic reward system. Recent literature indicates that galanin blocks MOR-mediated dopamine release in the VTA via GalR1-MOR heteromer interactions. Recently, our lab found that intra-VTA galanin administration attenuates morphine conditioned place preference (CPP) in male and female mice, identifying a neuroanatomical substrate for galanin action in opioid reward. However, the mechanisms underlying galanin’s ability to attenuate morphine CPP are not clear. Thus, the proposed experiments were designed with 2 key goals: 1) identify the source of endogenous galanin in the VTA that opposes opioid signaling, and 2) determine the role of the GalR1-MOR heteromer in the VTA in opioid reward. The overarching hypothesis of this proposal is that galanin from the lateral hypothalamus (LH) signals through GalR1-MOR heteromers on GABAergic projections from the rostromedial tegmental nucleus (RMTg) within the VTA to oppose morphine CPP. A combination of behavioral, molecular, pharmacological, and genetic tools will be used to test this hypothesis in male and female mice. In Aim 1, I will use retrograde viral-assisted tracing and RNAscope in situ hybridization to determine all endogenous sources of galanin to the VTA. Then, I will ablate galanin in the LH, which we know contains galaninergic projections to the VTA and modulates opioid reward, by locally infusing Cre-expressing virus into the LH of floxed galanin conditional knockout mice and quantify the density of the galanin-positive fibers in the VTA. Additionally, morphine CPP will determine the consequences of removing LH galanin inputs to the VTA on opioid reward. In Aim 2, a validated GalR1-MOR heteromer interfering peptide will be co-infused with galanin into the VTA to determine whether local heteromer signaling is necessary for galanin to attenuate morphine CPP. Conversely, a novel viral construct will be used to overexpress GalR1 selectively in MOR-containing GABAergic neurons of the RMTg. Together, these experiments will provide crucial information regarding the role of galanin in opioid reward and have the potential to identify the GalR1-MOR heteromer as a novel therapeutic target in OUD. These experiments support the mission of NIDA to advance science on drug use and addiction and promote my development into an independent scientist who will continue to pursue this mission throughout my career.