CHRONIC LIRAGLUTIDE INDUCES PERSISTENT ADAPTATIONS IN HYDROSALINE REGULATION AND STRESS-COPING BEHAVIOR IN ADULT RATS

GLP-1R agonists are widely used to treat obesity and metabolic disease. GLP-1 signaling interacts with neuroendocrine circuits involved in hydrosaline homeostasis, including vasopressin-regulated pathways. Whether chronic GLP-1R activation induces persistent, plastic adaptations in hydroelectrolitic regulation remains unknown. We evaluated the effects of chronic liraglutide treatment on hydrosaline regulation and neuroendocrine stress-related behaviors in adult rats.
Adult male and female rats received liraglutide for six weeks. Body weight, food and water intake, urinary osmolality, and sodium concentrations were monitored throughout treatment. To assess persistent adaptations, a 24 h drug withdrawal period followed by a 24 h water deprivation challenge (WD24h) was performed. Urinary and plasma osmolality and sodium concentrations were measured at the beginning and end of the WD24h. Furosemide-treated rats were included as a physiological comparator. Chronic liraglutide treatment induced a marked impairment in urinary concentrating capacity. Critically, altered plasma osmolarity regulation was unmasked after water deprivation, consistent with long-term neuroendocrine reprogramming. Urinary Na-concentrations were within physiological ranges at the beginning of the WD24h protocol but increased after dehydration. Plasma osmolarity was similar to that of the controls at baseline but increased after WD24h. Spatial learning, memory, and locomotion were preserved; a sex-dependent reduction in immobility in the forced swim test was observed.
These findings identify GLP-1R signaling as a modulator of long-term neuroendocrine control of fluid and electrolyte balance. Subtle sex-dependent effects of chronic treatment were observed after drug withdrawal, consistent with durable functional adaptations in circuits responsible for homeostatic and allostatic regulation of water balance.
Funding: UNAM-PAPIIT (IT200125).