Hormones, Stress and Depression
Every disturbance of the body, either real or imagined, evokes a stress response. Essential to this stress response is the activation of the hypothalamic-pituitary-adrenocortical (HPA) system, finally resulting in the release of glucocorticoid hormones from the adrenal cortex. Glucocorticoid hormones, in turn, feed back to this system by central activation of two types of corticosteroid receptors: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Whereas a brief period of controllable stress, experienced with general arousal and excitement, can be a challenge and might thus be beneficial, chronically elevated levels of circulating corticosteroid hormones are believed to enhance vulnerability to a variety of diseases, including human affective disorders.
The cumulative evidence makes a strong case implicating corticosteroid receptor dysfunction in the pathogenesis of affective disorders. Corticosteroid receptor dysfunction is followed by changes in the sensitivity of the system to the inhibitory effects of glucocorticoids on the synthesis of CRH and vasopressin in hypothalamic neurons. Changes in CRH and vasopressin levels, in turn, determine the responsiveness of the axis to subsequent stressors: increased production of these neuropeptides leads to increased HPA responses to stress and might be associated with an enhanced anxiety state. Although definitive controlled trials remain to be conducted, there is evidence indicating that cortisol-lowering or corticosteroid receptor antagonist treatments, as well as CRH type 1 receptor antagonists, may be of clinical benefit in individuals with major depression. Therefore, a more detailed knowledge of GR and CRH receptor signalling pathways will ultimately lead to the development of novel neuropharmacological intervention strategies.
KeywordsGlucocorticoid Receptor Mineralocorticoid Receptor Dexamethasone Suppression Test Corticosteroid Receptor Corticosteroid Hormone
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- Heuser IJE, Schweiger U, Gotthardt U, Schmider J, Lammers CH, Dettling M, Yassouridis A, Holsboer F (1996) Pituitary-adrenal system regulation and psychopathology during amitriptyline treatment in elderly depressed patients and in normal control subjects. Am J Psychiat 153: 93–99.PubMedGoogle Scholar
- Holsboer F (1995) Neuroendocrinology of mood disorders. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: The fourth generation of progress. Raven Press, New York, pp. 957–968.Google Scholar
- Meijer OC, de Boer AG, van der Sandt ICJ, de Lange ECM, De Kloet ER (2000) The multidrug resistance 1A P-glycoprotein affects the penetration of glucocorticoids, except corticosterone, in the brain. Soc Neurosci Abstr 26: 419.Google Scholar
- Morisette J, Villeenuve A, Lordeleau L, Rochette D, Laberge C, Gagné B, Laprise C, Bouchard G, Plante M, Gobeil L, Shink E, Weissenbach J, Barden N (1999) Genome-wide search for linkage of bipolar affective disorders in a very large pedigree derived from a homogenous population in Quebec points to a locus of major affect on chromosome 12q23–q24. Am J Med Genet 88: 567–587.CrossRefPubMedGoogle Scholar
- Müller MB, Landgraf R, Sillaber I, Kresse AE, Keck ME, Zimmermann S, Holsboer F, Wurst W (2000) Selective activation of the hypothalamic vasopressinergic system in mice deficient for the corticotropin-releasing hormone receptor 1 is dependent on glucocorticoids. Endocrinology 141: 4262–4269.CrossRefPubMedGoogle Scholar
- Müller MB, Keck ME, Binder EB, Kresse AE, Hagemeyer TP, Landgraf R, Holsboer F, Uhr M (2003a) ABCB1-(MDR1)-type P-glycoproteins at the blood-brain barrier modulate the activity of the hypothalamic-pituitary-adrenocortical system: implications for affective disorder. Neurospychopharmacology 28: 1991–1999.Google Scholar
- Müller MB, Zimmermann S, Sillaber I, Hagemeyer TP, Deussing JM, Timpl P, Kormann MSD, Droste S, Kühn R, Reul JMHM, Holsboer F, Wurst W (2003b) Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nature Neurosci 6: 1100–1107.CrossRefPubMedGoogle Scholar
- Selye H (1946) The general adaptation syndrome and the diseases of adaptation. J Clin Endocrinol 6: 117–196.Google Scholar
- Smith GW, Aubry J-M, Dellu F, Contarino A, Bilezikijan LM, Gold LH, Chen R, Marchuk Y, Hauser C, Bentley CA, Sawchenko PE, Koob GF, Vale W, Lee K-F (1998) Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20: 1093–1102.CrossRefPubMedGoogle Scholar
- van Rossum EF, Koper JW, Huizenga NA, Uitterlinden AG, Janssen JA, O. BA, Grobbee DE, de Jong FH, van Duyn CM, A. PH, Lamberts SW (2002) A polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels. Diabetes 51: 3128–3134.PubMedGoogle Scholar