Selective blockade of the mineralocorticoid receptor impairs hypothalamic-pituitary-adrenal axis expression of habituation

The present study investigated the role of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) in the expression of habituation of the hypothalamic-pituitary-adrenal (HPA) axis response to stress. Male rats wer e restrained for 1 h per day for six consecutive days. On day 6, 1 h prior to restraint stress, both restraint-naive and repeatedly restrained rats we re injected s.c. with either vehicle (propylene glycol) or one of three cor ticosteroid receptor antagonist treatments: selective MR antagonist (RU2831 8 or spironolactone), selective GR antagonist (RU40555), or both MR and GR antagonists combined (RU28318 + RU40555). Blood samples were collected for corticosterone measurement at the beginning of stress, during stress, and 1 h after stress termination. Repeated restraint stress produced significant habituation of corticosterone responses. Acute treatment with the combined MR and GR antagonists prevented the expression of habituation. When tested alone, the MR antagonist also blocked the expression of corticosterone-res ponse habituation, whereas the GR antagonist had no effect. Neither the MR, nor the GR antagonists alone, significantly altered the corticosterone res ponse to restraint in rats exposed to restraint for the first time. The fin al experiment examined the corticosterone response to a corticotropin relea sing hormone (CRH, 3 mu g/kg i.p.) challenge. Neither previous exposure to restraint or acute pretreatment with the combined MR and GR antagonists (RU 28318 + RU40555) altered the corticosterone response to CRH challenge. This result indicates that the expression of habituation and its blockade by co rticosteroid receptor antagonists is not a result of altered pituitary-adre nal response to CRH. Overall, this study suggests that MR plays an importan t role in constraining the HPA axis response to restraint stress in restrai nt-habituated rats. The dependence of the HPA axis on MR-mediated corticost eroid negative feedback during acute stress may be an important mechanism t hat helps maximize the expression of stress habituation and thereby minimiz e exposure of target tissues to corticosteroids in the context of repeated stress.