F. Paliarin, E. Doré, P. Panthagani, S. Mirza, L. Finlay, T. Nguyen, E. Weiser, C. Duplantis, and R. Maiya

Social stress is a critical driver of escalated alcohol use and relapse; however, the associated molecular mechanisms are poorly understood, limiting the identification and evaluation of therapeutic targets. We have demonstrated using Social Defeat Stress (SDS) model that alcohol consumption was escalated in both male and female C57BL/6J mice. Stress related behaviors have been shown to be mediated via Dynorphin/Kappa opioid receptor (Dyn/KOR) system. When administered systemically with a long-acting KOR antagonist like Norbinaltorphimine (NorBNI), both male and female stress animals reduced alcohol consumption, with minimal effect on unstressed controls. Stress escalated alcohol consumption was ameliorated in Oprk1-Cre male mice after chemogenetic activation of KOR expressing neurons in Basolateral Amygdala (BLA^KOR). Both KOR antagonism and chemogenetic activation of BLA^KOR terminals in Bed Nucleus of Stria Terminalis (BNST) attenuated escalation of alcohol consumption in both males and females, implicating the BLA^KOR-BNST pathway in SDS induced drinking. In line with these findings, we found that, KOR deletion in the BLA diminished SDS-escalated alcohol consumption in female mice. We further observed increased prodynorphine (pDyn) expression in Dorsal raphe nucleus (DRN) and enhanced activation of BNST-projecting DRN^Dyn neurons following social stress, suggesting these neurons as a key source of Dyn recruited by SDS. Future experiments will examine the causal role of DRN^Dyn neurons in SDS-induced alcohol escalation following deletion of KOR in BLA-BNST pathway.

Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA

Funding: R01AA031733, R01AA027293 and LSUHSC startup funds.