A brain–pancreas circuit for regulation of alcohol intake in female mice

Alcohol (EtOH) dysregulates brain–body signals linking satiety and reward, but the mechanisms remain ambiguous. Insulin, a metabolic and anabolic hormone produced in the pancreas, regulates central reward and satiety circuits and is disrupted by EtOH. Pancreas-projecting parasympathetic neurons in the dorsal motor nucleus of the vagus (DMV PP ) stimulate insulin release and are inhibited by acute EtOH administration. Here, we sought to determine impacts of short-term EtOH intake and exposure on the DMV-pancreas axis and test the hypothesis that stimulation of the DMV-pancreas axis decreases EtOH intake. Adult female C57BL/6J mice exposed to 3-days of chronic intermittent ethanol (CIE) vapor had reduced fasting plasma insulin, increased fasting blood glucose, and elevated immunostaining of pancreatic insulin at 4 h of withdrawal. Chemogenetic activation of DMV PP neurons reduced pancreatic insulin accumulation and decreased voluntary two-bottle choice EtOH intake after CIE. Intranasal insulin delivery similarly reduced EtOH intake and preference after CIE, indicating central mechanisms. These findings suggest EtOH disrupts DMV PP function and that restoring components of the brain-pancreas axis reduces EtOH intake in the fasted state. Together, these findings identify a brain-pancreas circuit that may link insulin with EtOH intake and highlight insulin-centric interventions as promising, testable strategies for future treatment development.