New mode of hypothalamic-pituitary-adrenocortical axis regulation: significance for stress-related disorders

Journal/Book: Z Rheumatol 1999; 58: 296-297. 1999;

Abstract: J. M. H. M. Reul; Max-Planck-Institut für Psychiatrie Deutsche Forschungsanstalt für Psychiatrie München The end-product of the hypothalamic-pituitary-adrenocortical(HPA)axis glucocorticoid hormones play a vital role in the control of homeostatic and adaptive processes activated by stressful challenges. These processes include metabolic immune (1) neural and behavioral (2) mechanisms. However not only after stress but also at baseline and throughout the circadian cycle glucocorticoids affect many physiological and behavioral processes (2). The main driving force of the HPA axis constitutes corticotropin-releasing hormone (CRH) expressed in parvocellular neurons of the hypothalamic paraventricular nucleus (PVN). This was further epitomized in mutant mice lacking a functional CRH receptor type 1 (CRH-R1). These animals were unable to generate a stress response in terms of rises in circulating ACTH and corticosterone levels (3). Moreover CRH-R1 mutant mice at any time of the day showed virtually undetectable levels of total (3) and free (4) corticosterone in the face of normal circulating ACTH levels. This observation is in line with the concept that adrenocortical sensitivity to ACTH is modulated by (CRH-R1-regulated) adrenomedullary sympathetic input. Given its role in numerous bodily functions a tight regulation of HPA axis activity both at baseline and after stress is critical for maintaining physical and mental health. A chronic hyper- as well as a hypofunction of this neuroendocrine system is thought to increase susceptibility for acquiring many diseases including infectious autoimmune and mental illnesses. Prime controllers of the HPA axis present the brain glucocorticoid-binding receptors i.e. the mineralocorticoid (MR) and the glucocorticoid receptor (GR) (5). Whereas GRs are ubiquitously localized in the brain the localization of MRs is almost restricted to the hippocampus where they subserve the tonic inhibitory influence of this limbic structure on HPA axis activity. ... le

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