SUN-012 HPA Axis Dynamics During Chronic Corticosterone Exposure

Abstract Disclosure: C. Ratner: Cecilia Ratner is emplyoed at Lundbeck A/S. V. Nielsen: Vibeke Nielsen is employed at Lundbeck A/S. M. Lubas: Michal Lubas is employed at Lundbeck A/S. M. Grupe Frost: Morten Grupe Frost is employed at Lundbeck A/S. A. Asuni: Ayodeji Asuni is employed at Lundbeck A/S. Elevated systemic glucocorticoid levels often result from exogenous glucocorticoid therapy, certain endocrine disorders such as Cushing’s syndrome and Cushing’s disease or in some psychiatric disorders with hypothalamic pituitary adrenal (HPA) axis overactivity including certain types of depression. In the present study, we aimed to assess how different treatment paradigms of chronic excess of glucocorticoids influence the dynamics of the HPA axis in a mouse model of exogenous corticosterone (CORT) treatment. CORT was administered to male C57Bl6/J mice for a duration of 21 days using three different treatment paradigms: Via the drinking water (80µg/ml), by subcutaneous pellet (7.5mg over 21 days) or by a combination of water (26.7µg/ml) and pellet (5mg over 21 days). Body weight was recorded throughout the study. Blood was sampled on day 7 and day 15 in the early light phase and just before lights out for CORT measurements. Mice were sacrificed on day 24 and pituitary glands were collected for gene expression analysis.To assess the reactivity of the HPA axis a separate cohort of mice treated with CORT pellets were subjected to acute restraint stress for 30 min on day 25 (4 days after end of CORT treatment). CORT treatment led to significantly lower body weight in some groups at select time points, but all groups showed trends toward lower body weight compared to control mice. All three types of CORT treatment resulted in increased plasma CORT levels in the early light phase on day 7 and day 15 compared to controls, while dark phase plasma CORT was similar between all groups. Overall, CORT levels were similar between the three treatment paradigms, but the water CORT group showed larger variability. CORT treatment reduced pituitary corticotropin releasing hormone receptor 1 (CRHR1) mRNA levels with no effect on proopiomelanocortin or glucocorticoid receptor mRNA levels. Treatment with CORT in the water reduced the vasopressin 1b receptor mRNA levels, which may be due to lower overall water intake. CORT treatment by subcutaneous pellets completely blocked the reactivity of the HPA axis to acute restraint stress. Overall, the three CORT treatment paradigms gave rise to similar results. The pellet treatment may be advantageous to obtain less variability in the model due to differences in water intake. CORT treatment gave rise to changes in the HPA axis including a significant downregulation of CRHR1, which may contribute to the lack of responsivity to acute stressors Presentation: Sunday, July 13, 2025