BLA^KORinputs to the BNST regulate social stress-escalated alcohol consumption

Abstract

Background: Aversive social experiences can lead to escalated drug consumption and increase the risk of relapse to drug seeking. Individuals who consume alcohol to alleviate the effects of social stress are more likely to develop an alcohol use disorder (AUD). Repeated social defeat stress (SDS) enhances the rewarding and reinforcing effects of alcohol. However, the neural mechanisms that underlie social stress-escalated alcohol drinking are not well understood. Here we explored the role of the dynorphin/kappa opioid receptor (Dyn/KOR) system in regulating social stress-escalated alcohol consumption. Methods: Male and female mice were subjected to repeated SDS for 10 days following which they were left undisturbed in their home cages. They were then subject to intermittent access (IA) two-bottle choice alcohol consumption procedure. The effects of systemic and BNST-specific KOR antagonism using the selective KOR antagonist NorBNI on stress-escalated drinking were evaluated. Using chemogenetic approaches inOprk1-Cremice, we examined the role of KOR expressing cells in the basolateral amygdala (BLAKORs) and BLAKOR-BNST pathway in social stress-escalated alcohol consumption. Results: Repeated SDS increased alcohol consumption and preference in both males and females. Systemic KOR antagonism attenuated SDS- escalated alcohol consumption in both males and females. BNST -specific KOR antagonism also attenuated stress-escalated drinking in males. Finally, selective chemogenetic activation of BLAKORsand BKAKOR-BNST pathway attenuated social stress-escalated alcohol consumption in both sexes. Conclusion: Our results suggest a significant role for BLAKORprojections to the BNST in regulating social stress-escalated alcohol consumption. Our results provide further evidence that the Dyn/KOR system maybe a viable target for medications development to treat comorbid stress and AUD.