Preclinical approaches for advancing precision applications of kappa-opioid receptor ligands in AUD treatment

Project Summary Although severe adverse consequences only occur in a subset of drinkers, alcohol abuse remains an ongoing global health crisis linked to more than 5% of all premature deaths worldwide. In addition to wide individual differences in susceptibility to developing an alcohol use disorder (AUD), there is increasing recognition that AUD represents a wide spectrum of symptomatology and underlying pathophysiology which can vary across individuals and throughout disease progression. As such, precision treatment strategies for AUD would be of great utility, but individual differences in the efficacy of putative pharmacotherapeutic interventions have gone largely understudied in preclinical models. The kappa-opioid receptor (KOR) system is a promising target for precision applications, given that multiple widely prescribed treatments for AUD have significant KOR affinity, and a range of KOR ligands are already in use for other disorders or in various stages of the clinical pipeline. The goals of this proposal are to 1) understand the relationship between the actions of KOR ligands on specific aspects of AUD-associated behaviors and 2) extend our basic understanding of the brain region-specific loci and the neurophysiological mechanisms underlying KOR regulation of individual differences in drinking behaviors. We approach these goals using operant alcohol self-administration in male and female mice, systemic and site- specific pharmacology as well as ex vivo multi-photon microscopy and optopharmacology. Together, by determining the behavioral impact of systemic pharmacological interventions as well as the neurophysiological impact of spatiotemporally discrete manipulations, this proposal will build foundational preclinical knowledge needed to advance precision targeting of the KOR system.