Synergistic-like decreases in alcohol intake following combined pharmacotherapy with GLP-1 and amylin in male rats.

Background And Purpose: The limited effectiveness of current pharmacological treatments for alcohol use disorder (AUD) highlights the need for novel therapies. These may involve the glucagon-like peptide-1 receptor or the amylin receptor, as treatment with agonists targeting either of these receptors lowers alcohol intake. The complexity of the mechanisms underlying AUD indicates that combining agents could enhance treatment efficacy. While a combination of amylin receptor and GLP-1 receptor agonists reduced food intake and body weight synergistic-like, its influence on alcohol intake is unknown.

Experimental Approach: Effects of a range of dose-combinations of GLP-1 receptor (dulaglutide) and amylin receptor (salmon calcitonin; sCT) agonists on alcohol intake were explored in male and female rats. We used dose combinations that either lowered alcohol intake as monotherapy (0.1 mg·kg + 5 μg·kg), or that did not affect alcohol consumption per se (0.075 mg·kg + 2 μg·kg).

Key Results: Acute administration of dulaglutide and sCT (0.1 mg·kg + 5 μg·kg) reduced alcohol intake in males, but not in females. When higher doses were evaluated in female rats, a decrease in alcohol intake was observed. Furthermore, the low dose combination (0.075 mg·kg + 2 μg·kg) decreased, in in a synergistic-like manner, alcohol intake and prevented abstinence-induced drinking without affecting kaolin intake in males. However, tolerance developed during sub-chronic treatment.

Conclusion And Implications: Collectively, these findings show that the combination of dulaglutide and sCT decreased, in in a synergistic-like manner, alcohol consumption in male rats. Contrarily, higher doses are required for females.