Resetting the Stress System with a Mifepristone Challenge

Cellular and Molecular Neurobiology
Sergiu DalmE R de Kloet

Abstract

Psychotic depression is characterized by elevated circulating cortisol, and high daily doses of the glucocorticoid/progesterone antagonist mifepristone for 1 week are required for significant improvement. Using a rodent model, we find that such high doses of mifepristone are needed because the antagonist is rapidly degraded and poorly penetrates the blood-brain barrier, but seems to facilitate the entry of cortisol. We also report that in male C57BL/6J mice, after a 7-day treatment with a high dose of mifepristone, basal blood corticosterone levels were similar to that of vehicle controls. This is surprising because after the first mifepristone challenge, corticosterone remained elevated for about 16 h, and then decreased towards vehicle control levels at 24 h. At that time, stress-induced corticosterone levels of the 1xMIF were sevenfold higher than the 7xMIF group, the latter response being twofold lower than controls. The 1xMIF mice showed behavioral hyperactivity during exploration of the circular hole board, while the 7xMIF mice rather engaged in serial search patterns. To explain this rapid reset of corticosterone secretion upon recurrent mifepristone administration, we suggest the following: (i) A rebound glucocorticoid ...Continue Reading

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Citations

Dec 24, 2018·Journal of Neuroendocrinology·Edo R de KloetAnnette D de Kloet
Jul 19, 2019·International Journal of Molecular Sciences·Katherine R Knox-ConcepcionLubo Zhang
Apr 4, 2019·Cellular and Molecular Neurobiology·Alejandro F De Nicola, Maria Claudia Gonzalez Deniselle
Apr 5, 2020·International Journal of Molecular Sciences·Alejandro F De NicolaMaria Claudia Gonzalez Deniselle
Feb 7, 2021·The European Journal of Neuroscience·Marc L Molendijk, E Ronald de Kloet
Mar 2, 2021·Neuropharmacology·M Adrienne McGinnLeandro F Vendruscolo
Nov 2, 2019·Neuroscience and Biobehavioral Reviews·Erik H Douma, E Ronald de Kloet

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