CORTICOSTERONE, BRAIN MINERALOCORTICOID-RECEPTORS (MRS) AND THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS - THE LEWIS RAT AS AN EXAMPLE OF INCREASED CENTRAL MR-CAPACITY AND A HYPORESPONSIVE HPA-AXIS

In this study we report a series of differences in brain and periphera l elements regulating the hypothalamic-pituitary-adrenal (HPA) axis be tween male LEW and Wistar rats. We found: (i) differential properties of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs ) in the brain (hippocampus, hypothalamus) and pituitary: LEW rats dis played an increased capacity of MRs in the hippocampus and hypothalamu s and a decreased capacity of glucocorticoid receptors GRs in the pitu itary. The binding affinity (Kd) for MRs and GRs in the hippocampus wa s comparable. (ii) Lower concentrations of corticotropin releasing hor mone (CRH) mRNA were detected in the nucleus paraventicularis of the h ypothalamus of LEW rats. (iii) Adrenal weight was similar in LEW and W istar rats; however, LEW rats had. about 30% less adrenocortical cells . Subjecting adrenocortical cells to increasing doses of ACTH(1-24) in vitro resulted in about a 60% smaller release of corticosterone in LE W rats. (iv) LEW rats escaped dexamethasone suppression showing increa sed basal levels of endogenous ACTH, but responded with a comparable r elease of corticosterone to the IV injection of 5 ng ACTH(1-24). (v) L EW rats responded to a variety of stimuli: adrenalectomy under ether a naesthesia, a novel environment, a tail nick and restraint or an immun ological challenge, with lower circulating ACTH and corticosterone pla sma levels than Wistar rats. (vi) Evening levels of ACTH and corticost erone were lower in LEW than Wistar rats but did not differ in the mor ning. Blockade of brain MRs in the evening by a central injection of t he specific MR antagonist RU28318 in LEW rats resulted in increased ci rculating levels of ACTH and corticosterone. (vii) Levels of corticost eroid-binding proteins were lower in one-day adrenalectomized LEW rats , indicating higher levels of free corticosterone. (viii) LEW rats had a smaller thymus than Wistar rats. Taken together, the receptor bindi ng data correspond to a decreased neuroendocrine responsiveness of LEW rats to stress. We suggest that the shift in the central MR/GR balanc e of LEW rats, i.e. augmented MR-mediated effects of corticosterone, i s the central regulating mechanism of the hyporeactive HPA axis in thi s rat strain. Lower levels of CRH mRNA in the hypothalamus and lower l evels of ACTH and corticosterone in response to various stimuli, as we ll as the hyporesponsive adrenals to exogenous ACTH, are apparently th e consequences of the life-long suppressive action of corticosterone v ia central MRs.