The glucagon-like peptide-1 receptor agonist, Ex4, reduces intromission in sexually experienced male mice

The physiological effects of glucagon-like peptide-1 (GLP-1) are vast, including food and glucose homeostasis. As the half-life is short, both short-acting, exendin-4 (Ex4) and long-acting, liraglutide and dulaglutide, GLP-1 receptor (GLP-1R) agonists have been developed and are approved for type 2 diabetes and/or obesity. They have also been found to reduce behaviors linked to addictive drugs through involvement of mesolimbic brain regions such as the medial amygdala. Additionally, Ex4 reduces sexual interactions in sexually naïve male mice and experienced females. However, the effects of GLP-1, short- and long-acting GLP-1R agonists on sexual behaviors in sexually experienced males remain unknown. Therefore, we examined how GLP-1 and Ex4 affect sexual behavior in experienced male mice, influenced associated neurochemical changes in the medial amygdala, and evaluated the potential modulatory factors through social behaviors. Additionally, we assess whether long-acting GLP-1R agonists impacted similar behaviors as well as the levels of corticosterone and insulin. Ex4 reducced the number of intromissions and ejaculations in sexually experienced male mice without GLP-1 having an effect. Moreover, social behaviors were unaffected by short-acting GLP-1R agonists. In the medial amygdala of these male mice treated with Ex4, the levels of glutamate and other amino acids were lower. Conversely, liraglutide and dulaglutide did not modify sexual behaviors but enhanced time in the social zone, with no effect on corticosterone or insulin levels. Together, these studies suggest that GLP-1R activation modulates both sexual and social behaviors, but the outcome depends on which agonists have been used.