Glucagon-Like Peptide-1 Receptors in Nucleus Accumbens, Ventral Hippocampus, and Lateral Septum Reduce Alcohol Reinforcement in Mice

Glucagon-like peptide 1 (GLP-1) receptor agonists can decrease alcohol intake by central mechanisms that are still poorly understood. The lateral septum (LS) and the ventral/caudal part of the hippocampus are enriched in GLP-1 receptors, and activity in these regions was shown to modulate reward-related behaviors. Using microinfusions of the GLP-1 receptor agonist exendin-4 in mice trained to self-administer oral alcohol in an operant assay, we tested whether pharmacological stimulation of GLP-1 receptors in hippocampus and LS decrease alcohol self-administration. We report that infusion of exendin-4 in the ventral hippocampus or LS was sufficient to reduce alcohol self-administration with as large effect sizes as we previously reported with systemic exendin-4 administration. Infusion of exendin-4 into the nucleus accumbens also reduced alcohol self-administration, as anticipated based on earlier reports, while infusion of exendin-4 into the caudateputamen (dorsal striatum) had little effect, consistent with lack of GLP-1 receptor expression in this region. The distribution of exendin-4 after infusion into the LS or caudate putamen was visualized using a fluorescently labeled ligand. These findings add to our understanding of the circuit-level mechanisms underlying the ability of GLP-1 receptor agonists to reduce alcohol self-administration.