GLP-1 and Alcohol-Related Behaviors: Insights From Preclinical Studies

Glucagon-like peptide-1 (GLP-1) has gained attention for its broad physiological effects, and both short-acting (exenatide/exendin-4 [Ex4]) and long-acting (liraglutide, dulaglutide, semaglutide) GLP-1 receptor (GLP-1R) agonists have been approved for type 2 diabetes and/or obesity. Initial preclinical research has highlighted the role of GLP-1 and its receptor in the pathophysiology of alcohol use disorder (AUD) and their potential use in the treatment of AUD. Specifically, systemic treatment of Ex4 reduces alcohol intake, the motivation to consume alcohol, and relapse-like behavior in male animals. Similarly, alcohol consummatory behaviors are reduced in male or female animals treated with either of the long-acting GLP-1R agonists. Moreover, both short- and long-acting GLP-1R agonists consistently attenuate the rewarding properties of alcohol, as measured by locomotor stimulation, dopamine release in the nucleus accumbens, and conditioned place preference in male mice. Because alcohol consumption is largely driven by alcohol-induced reward, it is hypothesized that GLP-1R agonists attenuate the rewarding effects of alcohol, thereby decreasing alcohol intake. However, it should be emphasized that other factors, including altered gastric emptying, nausea, and enhanced stress, may also contribute to these effects. Taken together, these preclinical studies offer insight into the potential use of GLP-1R agonists in the treatment of AUD.