Long-term treatment with a glucagon-like peptide-1 receptor agonist reduces ethanol intake in male and female rats

Given the limited efficacy of available pharmacotherapies for treatment of alcohol use disorder (AUD), the need for new medications is substantial. Preclinical studies have shown that acute administration of glucagon-like peptide-1 receptor (GLP-1R) agonists inhibits various ethanol-related behaviours, indicating this system as a potential target for AUD. However, the effects of long-term systemic treatment of GLP-1R agonists on ethanol intake in male and female rodents are to date unknown. Therefore, we investigated the effects of 9 or 5 weeks of once weekly administration of dulaglutide, a long-acting GLP-1R agonist, on ethanol intake in male and female rats. The ethanol intake during treatment discontinuation was also monitored. In an initial attempt to identify preliminary underlying mechanisms, the effects of 9 weeks of once weekly dulaglutide treatment on monoaminergic signalling in reward-related areas were explored in both sexes. We found that 9 or 5 weeks of once weekly dulaglutide treatment reduced ethanol intake and preference in male and female rats. Following discontinuation of dulaglutide treatment, the decrease in ethanol consumption was prolonged in males, but not females. We demonstrated that 9 weeks of dulaglutide treatment differentially influenced monoaminergic signalling in reward-related areas of male and female rats. Collectively, these data imply that the GLP-1R attracts interest as a potential molecular target in the medical treatment of AUD in humans: more specifically, dulaglutide should be evaluated as a potential medication for treatment thereof.