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Resetting the Stress System with a Mifepristone Challenge
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 antag...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469632/ https://www.ncbi.nlm.nih.gov/pubmed/30173378 http://dx.doi.org/10.1007/s10571-018-0614-5 |
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author | Dalm, Sergiu Karssen, Adriaan M. Meijer, Onno C. Belanoff, Joseph K. de Kloet, E. Ronald |
author_facet | Dalm, Sergiu Karssen, Adriaan M. Meijer, Onno C. Belanoff, Joseph K. de Kloet, E. Ronald |
author_sort | Dalm, Sergiu |
collection | PubMed |
description | 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 feedback after cessation of mifepristone treatment. (ii) Glucocorticoid agonism in transrepression and recruitment of cell-specific coregulator cocktails. (iii) A more prominent role of brain MR function in control of stress circuit activity. An overview table of neuroendocrine MIF effects is provided. The data are of interest for understanding the mechanistic underpinning of stress system reset as treatment strategy for stress-related diseases. |
format | Online Article Text |
id | pubmed-6469632 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-64696322019-05-03 Resetting the Stress System with a Mifepristone Challenge Dalm, Sergiu Karssen, Adriaan M. Meijer, Onno C. Belanoff, Joseph K. de Kloet, E. Ronald Cell Mol Neurobiol Review Paper 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 feedback after cessation of mifepristone treatment. (ii) Glucocorticoid agonism in transrepression and recruitment of cell-specific coregulator cocktails. (iii) A more prominent role of brain MR function in control of stress circuit activity. An overview table of neuroendocrine MIF effects is provided. The data are of interest for understanding the mechanistic underpinning of stress system reset as treatment strategy for stress-related diseases. Springer US 2018-09-01 2019 /pmc/articles/PMC6469632/ /pubmed/30173378 http://dx.doi.org/10.1007/s10571-018-0614-5 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Review Paper Dalm, Sergiu Karssen, Adriaan M. Meijer, Onno C. Belanoff, Joseph K. de Kloet, E. Ronald Resetting the Stress System with a Mifepristone Challenge |
title | Resetting the Stress System with a Mifepristone Challenge |
title_full | Resetting the Stress System with a Mifepristone Challenge |
title_fullStr | Resetting the Stress System with a Mifepristone Challenge |
title_full_unstemmed | Resetting the Stress System with a Mifepristone Challenge |
title_short | Resetting the Stress System with a Mifepristone Challenge |
title_sort | resetting the stress system with a mifepristone challenge |
topic | Review Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469632/ https://www.ncbi.nlm.nih.gov/pubmed/30173378 http://dx.doi.org/10.1007/s10571-018-0614-5 |
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