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Estradiol modulation of the renin–angiotensin system and the regulation of fear extinction

Post-traumatic stress disorder (PTSD) is more prevalent in women than men, yet much remains to be determined regarding the mechanism underlying this sex difference. Clinical and preclinical studies have shown that low estradiol levels during extinction of fear conditioning in rodents (i.e., cue expo...

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Autores principales: Parrish, Jenna N., Bertholomey, Megan L., Pang, Hong W., Speth, Robert C., Torregrossa, Mary M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351608/
https://www.ncbi.nlm.nih.gov/pubmed/30696810
http://dx.doi.org/10.1038/s41398-019-0374-0
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author Parrish, Jenna N.
Bertholomey, Megan L.
Pang, Hong W.
Speth, Robert C.
Torregrossa, Mary M.
author_facet Parrish, Jenna N.
Bertholomey, Megan L.
Pang, Hong W.
Speth, Robert C.
Torregrossa, Mary M.
author_sort Parrish, Jenna N.
collection PubMed
description Post-traumatic stress disorder (PTSD) is more prevalent in women than men, yet much remains to be determined regarding the mechanism underlying this sex difference. Clinical and preclinical studies have shown that low estradiol levels during extinction of fear conditioning in rodents (i.e., cue exposure therapy in humans) leads to poor extinction consolidation and increased fear during extinction recall. The renin–angiotensin system (RAS) is also associated with stress-related pathologies, and RAS antagonists can enhance extinction consolidation in males. However, less is known about how estradiol and the RAS converge to alter fear extinction consolidation in females. Since estradiol downregulates the RAS, we determined the role of surgically (via ovariectomy [OVX]) and pharmacologically (via the hormonal contraceptive [HC], levonorgestrel) clamping estradiol at low levels in female rats on fear-related behavior, serum estradiol and angiotensin II (Ang II) levels, and angiotensin II type I receptor (AT1R) binding in the brain. We then tested whether the AT1R antagonist losartan would alter fear-related behavior in an estradiol-dependent manner. We found that both OVX and HC treatment produced extinction consolidation deficits relative to intact female rats in proestrus (when estradiol levels are high), and that losartan treatment mitigated these deficits and reduced freezing. OVX, but not HC, altered AT1R ligand binding, though HC reduced estradiol and increased Ang II levels in plasma. These findings have significant clinical implications, indicating that administration of an AT1R antagonist, especially if estradiol levels are low, prior to an exposure therapy session may improve treatment outcomes in females.
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spelling pubmed-63516082019-02-06 Estradiol modulation of the renin–angiotensin system and the regulation of fear extinction Parrish, Jenna N. Bertholomey, Megan L. Pang, Hong W. Speth, Robert C. Torregrossa, Mary M. Transl Psychiatry Article Post-traumatic stress disorder (PTSD) is more prevalent in women than men, yet much remains to be determined regarding the mechanism underlying this sex difference. Clinical and preclinical studies have shown that low estradiol levels during extinction of fear conditioning in rodents (i.e., cue exposure therapy in humans) leads to poor extinction consolidation and increased fear during extinction recall. The renin–angiotensin system (RAS) is also associated with stress-related pathologies, and RAS antagonists can enhance extinction consolidation in males. However, less is known about how estradiol and the RAS converge to alter fear extinction consolidation in females. Since estradiol downregulates the RAS, we determined the role of surgically (via ovariectomy [OVX]) and pharmacologically (via the hormonal contraceptive [HC], levonorgestrel) clamping estradiol at low levels in female rats on fear-related behavior, serum estradiol and angiotensin II (Ang II) levels, and angiotensin II type I receptor (AT1R) binding in the brain. We then tested whether the AT1R antagonist losartan would alter fear-related behavior in an estradiol-dependent manner. We found that both OVX and HC treatment produced extinction consolidation deficits relative to intact female rats in proestrus (when estradiol levels are high), and that losartan treatment mitigated these deficits and reduced freezing. OVX, but not HC, altered AT1R ligand binding, though HC reduced estradiol and increased Ang II levels in plasma. These findings have significant clinical implications, indicating that administration of an AT1R antagonist, especially if estradiol levels are low, prior to an exposure therapy session may improve treatment outcomes in females. Nature Publishing Group UK 2019-01-29 /pmc/articles/PMC6351608/ /pubmed/30696810 http://dx.doi.org/10.1038/s41398-019-0374-0 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Parrish, Jenna N.
Bertholomey, Megan L.
Pang, Hong W.
Speth, Robert C.
Torregrossa, Mary M.
Estradiol modulation of the renin–angiotensin system and the regulation of fear extinction
title Estradiol modulation of the renin–angiotensin system and the regulation of fear extinction
title_full Estradiol modulation of the renin–angiotensin system and the regulation of fear extinction
title_fullStr Estradiol modulation of the renin–angiotensin system and the regulation of fear extinction
title_full_unstemmed Estradiol modulation of the renin–angiotensin system and the regulation of fear extinction
title_short Estradiol modulation of the renin–angiotensin system and the regulation of fear extinction
title_sort estradiol modulation of the renin–angiotensin system and the regulation of fear extinction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351608/
https://www.ncbi.nlm.nih.gov/pubmed/30696810
http://dx.doi.org/10.1038/s41398-019-0374-0
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