Short- and long-acting GLP-1 receptor agonists decrease female sexual behaviors in experienced rodents

Beyond the metabolic effects induced by long- and short-acting glucagon-like peptide-1 receptor (GLP-1R) agonists, they modulate reward-related behaviors by acting on brain regions including lateral septum (LS) and neural pathways involving the nucleus tractus solitarii (NTS). While the short-acting GLP-1R agonist exendin-4 (Ex-4) reduces sexual behaviors in sexually naïve male mice, the effects of long- versus short-acting GLP-1R agonists on natural rewards, such as sexual and social behaviors, in females remain unexplored. In the current study, we investigate the effects of both long-acting (dulaglutide, liraglutide) and short-acting (Ex-4) GLP-1R agonists on sexual and social behaviors in sexually experienced female rats and mice. While the GLP-1R agonists decreased sexual behaviors in females, they appear to be drug- and species-specific. In female rats, Ex-4 reduced the time with the males, the number of mounts, intromissions, ejaculations, darts and hops, as well as the lordosis intensity. Female mice treated with liraglutide and dulaglutide display a reduction in time with male stimulatory mouse, and as a possible consequence, a lowered mounting and intromission duration, potentially involving increased noradrenaline levels in the NTS and altered glutamate, glutamine, and taurine levels in the LS. In the three-chamber test, dulaglutide decreased the social novelty, another behavior associated with reward/motivation. Moreover, the long-acting GLP-1R agonists increased sociability and the time to seek a novel object. These results highlight species-dependent and agonist-specific effects of GLP-1R activation on sexual and social function in females and expands our understanding of the broader role of GLP-1.