Association between chronic mild stress and repeated corticosterone administration in female mice: a double-hit model of depression?

Major depression is a disorder that affects around 280 million people worldwide. Several animal models were developed to study its pathophysiology. Models related to hypothalamic-pituitary-adrenal axis dysfunctions, like chronic unpredictable mild stress (CUMS) and repeated corticosterone administration, induce behavioral changes related to a depressive phenotype in rodents. However, those approaches were initially used in rats but lacked reproducibility in mice due to their high variability in stress response. Therefore, models that use combined interventions can be a useful tool to overcome this barrier. Thus, this study aimed to evaluate the behavioral alterations induced by a double intervention protocol, combining exposure to CUMS (restraint, strobe light, tilted or empty cage, wet bedding material, inverted dark/light cycle, food or water deprivation) and corticosterone administration. Adult female Swiss mice were divided into four groups: vehicle (s.c.), corticosterone (20mg/kg s.c.), CUMS (vehicle s.c. and CUMS), and combined model (20mg/kg corticosterone s.c. and CUMS) (CEUA/UFRJ 058/23). After three weeks of intervention, mice were submitted to behavioral assays: sucrose preference, splash test, social approach, elevated plus maze, tail suspension test, open field, and forced swimming test. Animals exposed to CUMS showed changes related to anxious and depressive phenotype, independently of the pharmacological treatment. Stress exposure decreased exploration of the plus maze open arms and open field center, increased grooming time in the splash test, and increased immobility in forced swimming. Overall, the effects of CUMS exposure overlapped those induced by corticosterone administration, which was unable to potentialize those alterations. Since this same CUMS protocol failed to induce behavioral changes previously, we believe that the daily injections acted as an additional stressor and amplified the stress response. Acknowledgments: FAPERJ, CAPES, CNPq.