An inhibitory GLP-1 circuit in the lateral septum modulates reward processing and alcohol intake in rodents.

BACKGROUND: Alcohol use disorder (AUD) is a complex psychiatric condition with limited effective treatment options. Glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as potential AUD treatment, as they have been shown to modulate reward-related behaviours, including those linked to alcohol consumption. However, the underlying mechanisms and neurocircuitry remain unclear. This study investigated the role of GLP-1R in the lateral septum (LS), a brain region highly expressing GLP-1R and implicated in reward-related behaviours, including alcohol-induced reward and consumption. METHODS: Behavioural, neurochemical, molecular, and electrophysiological methods were used to investigate the effect of LS GLP-1R signalling in alcohol-mediated responses in rodents. FINDINGS: LS GLP-1R activation attenuated alcohol's rewarding effects, reducing locomotor stimulation, place preference, and accumbal dopamine release. Intra-LS infusion of the GLP-1R agonist exendin-4 (Ex4) reduced alcohol intake dose-dependently without affecting food or water consumption, while GLP-1R inhibition increased alcohol intake. Furthermore, LS GLP-1R expression correlated with alcohol intake in male but not female rats, suggesting sex-specific effects of long-term alcohol exposure. Ex vivo electrophysiology indicated that GLP-1R activation depressed LS neurotransmission via a gamma-aminobutyric acid (GABA)(A) receptor-dependent mechanism. INTERPRETATION: This study provides new insights into how GLP-1R agonists may reduce alcohol intake. Overall, the findings underscore the potentially inhibitory neuromodulatory role of LS GLP-1R in regulating alcohol consumption through the modulation of dopaminergic reward processes tentatively involving GABA transmission. FUNDING: Swedish Research Council (2023-2600), Sahlgrenska University HospitalLUA/ALF (grant no. 723941), Adlerbertska Research Foundation and Professor Bror Gadelius Foundation.