title: Stress and Depression: a Crucial Role of the Mineralocorticoid Receptor.
abstract: Cortisol and corticosterone act on the appraisal process, which comprises the selection of an appropriate coping style and the encoding of the experience for storage in the memory. This action exerted by the stress hormones is mediated by mineralocorticoid receptors (MRs), which are expressed abundantly in the limbic circuitry, particularly in the hippocampus. Limbic MR is down-regulated by chronic stress and during depression but induced by antidepressants. Increased MR activity inhibits hypothalamic-pituitary-adrenal axis activity, promotes slow wave sleep, reduces anxiety and switches circuit connectivity to support coping. Cortisol and emotion-cognition are affected by MR gene haplotypes based on rs5522 and rs2070951. Haplotype 1 (GA) moderates the effects of (early) life stressors, reproductive cycle and oral contraceptives. MR haplotype 2 (CA) is a gain of function variant that protects females against depression by association with an optimistic, resilient phenotype. Activation of MR therefore may offer a target for alleviating depression and cognitive dysfunction. Accordingly, the MR agonist fludrocortisone was found to enhance the efficacy of antidepressants and to improve memory and executive functions in young depressed patients. In conclusion, CORT coordinates via MR the networks underlying how an individual copes with stress, and this action is complemented by the widely distributed lower affinity glucocorticoid receptor (GR) involved in the subsequent management of stress adaptation. In this MR:GR regulation, the MR is an important target for promoting resilience.
authors.affiliation: Division of Internal Medicine, Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: E R
authors.initials: ER
authors.lastname: de Kloet
authors.affiliation: Klinik für Psychiatrie und Psychotherapie, Charité Universitätsmedizin Campus Benjamin Franklin, Berlin, Germany.|NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Otte
authors.affiliation: Genetic Psychology, Fakultät für Psychologie, Ruhr-Universität Bochum, Bochum, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Kumsta
authors.affiliation: Department of Anesthesiology and Intensive Care, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Kok
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: M H J
authors.initials: MH
authors.lastname: Hillegers
authors.affiliation: Klinik für Psychiatrie und Psychotherapie, Charité Universitätsmedizin Campus Benjamin Franklin, Berlin, Germany.|NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Hasselmann
authors.affiliation: Department of Biological und Clinical Psychology, University of Trier, Trier, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Kliegel
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Joëls
mesh_terms: D000223:Adaptation, Psychological; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D003345:Corticosterone / Q000378:metabolism / Q000502:physiology*; D003863:Depression / Q000378:metabolism / Q000503:physiopathology*; D005438:Fludrocortisone / Q000627:therapeutic use; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011965:Receptors, Glucocorticoid / Q000378:metabolism / Q000502:physiology; D018161:Receptors, Mineralocorticoid / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D000928:Antidepressive Agents; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D005438:Fludrocortisone; D003345:Corticosterone
keywords: corticosterone; cortisol; depression; fludrocortisone; genetics; heart; hippocampus; mineralocorticoid receptors; stress