The role of vasopressin deficiency in the fluid intake suppression hyper-responsivity to central glucagon-like peptide-1 in the Brattleboro rat

Abstract

Food and fluid intakes are physiologically and behaviorally intertwined; one often affects the other. Likewise, pharmacological manipulations that influence eating often affect drinking. For example, glucagon-like peptide-1 (GLP-1) suppresses both eating and fluid intake, but the respective elements of the GLP-1 system remain unparsed. The Brattleboro rat has emerged as a model to test for separable elements in the control of fluid or food intake. Brattleboro rats have hereditary hypothalamic vasopressin deficiency. To compensate for the resultant polyuria, they drink copious amounts of water. Eating, however, is similar to that observed in wildtype littermates and other Long Evans rats. Interestingly, treatment with a GLP-1 receptor agonist exendin-4 (Ex4) causes an exaggerated suppression of drinking in Brattleboro rats, but suppression of eating is comparable to wildtype controls. To test if this hyper-responsivity depends on the polydipsia in these rats, we normalized their drinking using desmopressin (ddAVP), a V2R agonist, before treatment with Ex4. ddAVP attenuated, but did not completely prevent, the hyper-responsivity to Ex4. Conversely, we treated wildtype rats with acute or chronic tolvaptan, a V2R antagonist, which generated a Brattleboro-like polydipsia, but this did not recapitulate the hyper-responsivity to Ex4 observed in Brattleboro rats. Based on these results, we conclude that polydipsia alone is insufficient to generate a hyper-responsive fluid intake suppression by Ex4, and that Brattleboro rats have at least some persistent hyper-responsivity to Ex4, even after alleviation of their polydipsia. These results provide important context for future studies using Brattleboro rats to study the GLP-1 system.

Keywords: Diabetes insipidus; Fluid intake; Glucagon-like peptide-1; Polydipsia; Polyuria; Thirst; Vasopressin.