BLA kappa opioid receptor inputs to the BNST mediate social stress-induced increases in alcohol drinking

Abstract Aversive social experiences can increase alcohol consumption and precipitate relapse during abstinence. Individuals who drink to alleviate social stress are at a heightened risk for developing an alcohol use disorder (AUD). In rodents, repeated social defeat stress (SDS) enhances motivation to consume alcohol, yet the underlying neural mechanisms remain poorly understood. Here, we investigated the role of dynorphin/kappa opioid receptor (Dyn/KOR) signaling in regulating stress-induced increases in alcohol consumption. We show that repeated SDS increased alcohol intake and preference in both sexes, effects that were attenuated by systemic administration of the KOR antagonist norBNI or local administration of norBNI into the bed nucleus of the stria terminalis (BNST). Chemogenetic activation of basolateral amygdala (BLA) KOR-expressing neurons and their projections to the BNST, as well as knockdown of KORs in the BLA, attenuated increased alcohol consumption following SDS. At the molecular level, SDS increased Pdyn mRNA expression and selectively activated BNST-projecting dynorphin neurons in the dorsal raphe nucleus. Together, these findings support a working model where Dyn/KOR modulation of the BLA–BNST pathway is critical for increased alcohol drinking induced by social stress, while pointing to the DRN as a candidate upstream source of Dyn. Our results highlight Dyn/KOR systems as a promising therapeutic target for comorbid stress-related pathology and AUD.