The role of central amylin receptor in opioid-mediated behaviors

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Project Summary The opioid epidemic remains a major public health crisis in the U.S. Despite the effectiveness of current FDA- approved medications to treat opioid use disorder (OUD), there is still a high rate of relapse following detoxification. Thus, there is a critical need for conceptually new research investigating the neurobiological mechanisms underlying opioid taking and seeking that could lead to novel druggable targets. Our exciting preliminary studies indicate that systemic infusions of amylin, a satiation factor and neuropeptide, attenuate oxycodone self-administration and reinstatement at doses that do not alter food intake or compromise the antinociceptive effects of oxycodone. Consistent with these findings, activation of amylin receptors in the mesolimbic reward system is sufficient to reduce oxycodone self-administration and reinstatement. While our pilot studies highlight a novel neuropeptide system that could be targeted to reduce opioid taking and seeking, there are significant gaps in our understanding of central amylin receptors and their role in addiction-like behaviors. We recently began to identify cell type-specific patterns of amylin receptor expression in the brain and showed that amylin receptors are expressed on dopamine and GABA neurons in the ventral tegmental area (VTA), as well as dopamine d1 receptor (D1R) and dopamine d2 receptor (D2R) -expressing medium spiny neurons (MSNs) in the nucleus accumbens (NAc). One goal of this proposal is to build upon and expand our pilot studies by comprehensively defining the functional roles of cell type-specific VTA and NAc amylin receptors in opioid taking and seeking using viral-mediated methods in transgenic rats (Aim 1). We will also determine the individual contributions of these amylin receptor-expressing cell types to amylin's efficacy (Aim 1). Very little is known about the cellular and molecular mechanisms underlying the suppressive effects of amylin pharmacotherapy on voluntary drug taking and seeking. Therefore, we will combine viral-mediated gene delivery approaches with in vivo fiber photometry in transgenic rats to determine how amylin pharmacotherapy alters intracellular calcium dynamics in specific VTA and NAc cell types of oxycodone-experienced and drug- naïve rats in order to understand how activation of central amylin receptors alters midbrain and striatal circuits to suppress opioid taking and seeking (Aim 2). Finally, we will use an unbiased, single nuclei transcriptomics approach to characterize the effects of oxycodone alone and in combination with amylin pharmacotherapy on amylin receptor expression and differently expressed genes (DEGs) in all VTA and NAc cell populations (Aim 3). Findings from these studies will provide our first insights into how oxycodone alters amylin receptor expression and signaling in specific midbrain and striatal cell populations and identify opioid dysregulated genes that are putatively restored by amylin pharmacotherapy. Overall, the research proposed in this application will advance a novel framework for the development of pharmacotherapies aimed at targeting central amylin receptor-expressing cells to treat OUD.