Grace Trinity Young
Estradiol (E2) inhibits water intake, but the mechanisms underlying this effect remain unclear. Glucagon-like peptide-1 (GLP-1) also suppresses fluid intake, and accumulating evidence suggests that estradiol enhances behavioral sensitivity to GLP-1 receptor activation. Therefore, this thesis examined whether estradiol enhances the anti-dipsogenic effects of GLP-1 receptor activation and whether endogenous GLP-1 signaling contributes to estradiol-induced suppression of drinking behavior. Ovariectomized (OVX) female rats were treated with estradiol benzoate (EB) or vehicle and tested in both angiotensin II-induced (AngII) and water deprivation-induced drinking paradigms. The effects of the GLP-1 receptor agonist exendin-4 and antagonist exendin-9 on water intake and drinking microstructure were assessed. Exendin-4 reduced water intake, and estradiol enhanced sensitivity to its fluid-suppressive effects, resulting in greater and more prolonged suppression of drinking behavior. In contrast, although exendin-9 increased drinking behavior, blockade of endogenous GLP-1 receptors did not abolish or attenuate the anti-dipsogenic effects of estradiol in either drinking model. Drinking microstructure analyses further indicated that estradiol and GLP-1 receptor activation influenced distinct components of drinking behavior, with estradiol primarily affecting measures associated with satiation and GLP-1 receptor activation influencing measures linked to the orosensory control of drinking. Together, these findings demonstrate that estradiol enhances responsiveness to GLP-1 receptor activation but does not require endogenous GLP-1 signaling to suppress water intake. These results provide new insights into the interaction between ovarian hormones and GLP-1 signaling in regulating fluid balance and may have important clinical implications for understanding sex differences in responses to GLP-1 receptor agonists pharmacotherapies.