A Glucocorticoid receptor antagonist reduces hyperactivity of adolescent female rats exposed to the activity-based anorexia model

Anorexia Nervosa (AN) is a severe psychiatric disorder characterized by the combination of dietary restriction and compulsive physical activity, that affects mainly adolescent females. Despite a still unknown etiology, high cortisol plasma levels, index of a hyperactivated Hypothalamic-Pituitary- Adrenal (HPA) axis, were found in underweight AN patients. The main goal of our work was to investigate the involvement of the HPA axis and the stress-related mechanisms in the Hippocampus (Hip), a brain area that regulates the HPA axis response, in mediating food intake and hyperactivity in AN. To this end, we took advantage of the Activity-Based Anorexia (ABA) model, by exposing adolescent female rats to the combination of food restriction and physical activity for 5 days. Molecular analyses have been performed in the acute phase of the AN phenotype (postnatal day [P]42) and after 7 days of bodyweight recovery (P49). At P42, ABA animals showed increased corticosterone plasma levels, increased translocation of the Glucocorticoid Receptor (GR) into the nucleus and reduced FKBP5 protein levels in the Hip. At P49, these effects were reduced in ABA animals, suggesting a long-lasting impairment of the HPA axis response. Given the potential implication of a hyperactivated HPA axis in sustaining the food restriction-evoked hyperactivity in ABA animals, we treated ABA rats with 10mg/mL mifepristone, a GR antagonist, during the ABA induction and dissected the specific contribution of the ventral (v) and dorsal (d) Hip at P42. Interestingly, mifepristone significantly reduced wheel activity on the last day of the phenotype induction and reverted ABA-induced dysregulation of the GR system only in the vHip, by blunting the GR-nuclear translocation index and the expression of GR-responsive genes, such as Sgk1. Overall, these results suggest that the modulation of HPA axis might represent a potential target to reduce the food restricted-induced hyperactivity, thus discontinuing the vicious cycle of the pathology.