Kappa Opioid Receptor modulation of BLA inputs to the BNST and stress-escalated drinking

Abstract Humans are social animals and social relations are critical for proper human development. However, social interactions can also be stressful. Social stress is a critical risk factor for many psychiatric illnesses, including substance use disorders. Individuals who consume alcohol in negative social contexts to alleviate social stress show a higher likelihood of developing alcohol use disorder (AUD). Social stress is effectively modeled in animals through social defeat paradigms. Repeated social defeat stress (SDS) enhances the rewarding and reinforcing properties of several drugs of abuse, including alcohol, and is a reliable predictor of future drug use. However, the precise neural mechanisms by which SDS leads to increased alcohol consumption are not well understood. The neuropeptide Dynorphin (Dyn) and its receptor, the Kappa Opioid Receptor (KOR) have been implicated in stress-induced drug seeking and taking. Our preliminary results show that repeated SDS leads to robust increases in alcohol consumption and preference in both male and female C57BL/6J mice. Systemic injections of NorBNI, a selective KOR antagonist, attenuated social stress-escalated alcohol consumption in both sexes. To determine brain regions in which KORs are acting to mediate social stress-escalated alcohol consumption, we generated and characterized a novel Oprk1-Cre mouse line. We first focused on the basolateral amygdala (BLA), a known regulator of behavioral responses to stress and alcohol consumption that also expresses high levels of KORs. Chemogenetic activation of KOR expressing cells in the BLA (BLAKOR) attenuated social stress- escalated drinking. BLAKOR neurons send robust projections to the bed nucleus of the stria terminalis (BNST). BNST-specific antagonism of KORs attenuated social stress-escalated alcohol consumption. Further, chemogenetic activation of BLAKOR -BNST pathway also attenuated social stress-escalated drinking. SDS robustly activated cFos in pDyn cells in the dorsal raphe (DRNDyn), a region known to project to the BNST. Based on these results we hypothesize that SDS activates DRNDyn inputs to the BNST and that Dyn-mediated inhibition of BLAKOR terminals in the BNST underlies social stress-escalated alcohol consumption. In Aim 1, we will test the hypothesis that BLAKOR projections to the BNST regulate post-stress increases in alcohol consumption. In Aim 2, we will test the contribution of DRNDyn-BNST pathway to social stress-escalated drinking. Finally in Aim 3 we will use combined electrophysiology and optogenetic tools to test the prediction that SDS triggers Dyn- mediated inhibition of BLAKOR terminals in the BNST. Results from these studies will provide mechanistic insights into the link between psychosocial stressors and alcohol consumption and inform potential treatment strategies for individuals suffering from comorbid stress and AUD.