A septal inhibitory circuit constrains alcohol reward and mediates liraglutide's suppressive effects on alcohol intake in mice.

Alcohol use disorder (AUD) lacks effective brain-targeted treatments. Here, using mouse models, we show that glucagon-like peptide-1 receptor (GLP-1R) signaling in the dorsal lateral septum (dLS) regulates alcohol consumption and reward. Systemic administration of the GLP-1R agonist liraglutide decreased alcohol intake and ethanol-evoked dopamine release in the nucleus accumbens, requiring GLP-1R expression in the dLS. Alcohol consumption suppressed dLSGLP-1R neuronal activity, whereas liraglutide prevented alcohol-induced suppression of transient calcium dynamics. Inactivation of these neurons increased alcohol consumption and abolished the behavioral effects of liraglutide, whereas chemogenetic activation suppressed alcohol-directed behavior. Circuit-level analysis identified a local inhibitory projection from dLSGLP-1R neurons to estrogen receptor 1-expressing neurons in the ventral lateral septum (vLSEsr1 neurons), and targeted manipulation of this circuit confirmed its role in regulating alcohol intake. Together, these findings delineate a septal inhibitory circuit through which GLP-1R signaling modulates alcohol-related behaviors and highlight the dLS as a therapeutic target for AUD.