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Therapy Insight: is there an imbalanced response of mineralocorticoid and glucocorticoid receptors in depression?

Abstract

In severely depressed patients, emotional arousal, cognitive abnormality and vulnerability to psychotic episodes are linked to a hyperactive hypothalamic–pituitary–adrenal (HPA) axis and high levels of circulating cortisol. The susceptibility pathways underlying these disturbed brain functions are influenced by genetic factors, early-life priming experiences and later-life events. Cortisol is an important determinant in this so-called three hit model. The action of cortisol is protective, but can become harmful if exposure of susceptibility pathways to the stress hormone is excessive and sustained or inadequate. In this article we argue that this change in role of cortisol from protective into harmful depends on the functioning of the mineralocorticoid and glucocorticoid receptors and the context in which the organism experiences the stressor. Actions mediated by the mineralocorticoid and glucocorticoid receptors are complementary and operate in different time domains of the stress response: the mineralocorticoid receptor normally prevents stress-induced disturbances, but if such disturbances occur the glucocorticoid receptor helps the recovery process. An imbalance in these receptor-mediated actions is thought to increase vulnerability to stress-related psychiatric disorders in predisposed individuals. Correction of the imbalance between the mineralocorticoid receptor and the glucocorticoid receptor can, therefore, facilitate recovery processes still present in the diseased brain, provided that the right psychological context is offered to the individual.

Key Points

  • Corticosteroid action in the brain is mediated by the high-affinity mineralocorticoid receptors, which protect neurons in stress, and lower-affinity glucocorticoid receptors, which promote recovery of neurons

  • Corticosteroids are generally protective but become harmful in excessive or inadequate concentrations, a change that is thought to depend on the context in which the mineralocorticoid and glucocorticoid receptors operate in pathways susceptible to stress in the brain

  • The maturation of susceptibility pathways depends on genetic factors and can be shaped by epigenetic processes that depend on the maternal environment

  • Targets for intervention in phenotypes vulnerable to stress-related psychiatric disorders are found in corticosteroid-responsive susceptibility pathways in the brain; potential drugs include specific ligands for the receptors, which in future may discriminate between different modes of action—at the level of membranes, gene transactivation and transrepression

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Figure 1: The brain as regulator and target of corticosteroids.
Figure 2: Mechanism of action of glucocorticoid hormones and potential drug targets.
Figure 3: Variants in human MR and GR genes.

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Acknowledgements

The support of the Royal Netherlands Academy for Arts and Sciences, the Netherlands Science Foundation, the Human Frontiers Science Program and the EU Network of Excellence 'Lifespan' is gratefully acknowledged.

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Correspondence to E Ronald de Kloet.

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ER de Kloet is on the scientific advisory board and is a stockholder of Corcept Therapeutics Inc., and is on the scientific advisory board of Organon International. He conducts a collaborative research program with Lundbeck AG in the TopInstitute Pharma supported by the Ministry of Economic Affairs, The Netherlands. RH DeRijk and OC Meijer declared they have no competing interests.

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de Kloet, E., DeRijk, R. & Meijer, O. Therapy Insight: is there an imbalanced response of mineralocorticoid and glucocorticoid receptors in depression?. Nat Rev Endocrinol 3, 168–179 (2007). https://doi.org/10.1038/ncpendmet0403

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