Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as promising pharmacotherapeutics for alcohol use disorder (AUD). Here, we examined the effects of semaglutide, a long-acting GLP-1 receptor agonist, on alcohol intake and anxiety-related behaviors in Marchigian Sardinian alcohol-preferring rats, a model characterized by excessive alcohol intake and pronounced anxious and depressive-like phenotypes. Male and female rats were treated with semaglutide (0.001, 0.01 and 0.1 mg/kg, s.c.) and vehicle. Voluntary alcohol consumption was assessed using the two-bottle choice paradigm. Locomotion, anxiety, and stress responses were evaluated during withdrawal and in naïve rats, following administration of the highest dose of semaglutide (0.1 mg/kg). Furthermore, the acute effects of semaglutide on GABAergic transmission were assessed in the central nucleus of the amygdala and in the infralimbic (IL) medial pre-frontal cortex (mPFC) of naïve rats. Semaglutide reduced voluntary alcohol consumption in a dose-dependent manner, and it produced anxiolytic-like behaviors during withdrawal in the open field test. In naïve animals, semaglutide reduced locomotor activity, lowered blood glucose levels, and decreased fat mass and GABAergic transmission in the IL mPFC. Our findings support the use of the GLP-1 receptor agonist semaglutide as a promising pharmacotherapy for the treatment of AUD and its associated psychiatric symptoms.
