An inhibitory GLP-1 circuit in the lateral septum modulates reward processing and alcohol intake in rodents
Christian E. Edvardsson, Davide Cadeddu, Mia Ericson, Louise Adermark, Elisabet Jerlhag
Abstract
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 Hospital LUA/ALF (grant no. 723941), Adlerbertska Research Foundation and Professor Bror Gadelius Foundation.