Parrish, Jenna Nicole
(2017)
ESTRADIOL MODULATION OF THE RENIN ANGIOTENSIN SYSTEM AND THE
REGULATION OF FEAR EXTINCTION.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Low estradiol levels during extinction training lead to poor extinction consolidation and increased fear during extinction recall; however, the mechanism by which this occurs has not been identified. The renin angiotensin system (RAS), which is often studied in the context of blood pressure regulation and cardiovascular function, has recently been associated with the stress response and stress related pathologies. Antagonists of the angiotensin II type 1 receptor (AT1R), which are commonly prescribed to treat hypertension, reduce symptoms of posttraumatic stress disorder (PTSD) in humans and enhance extinction consolidation in male mice. Since estradiol downregulates many components of the RAS, including AT1R, we hypothesized that estradiol modulates the RAS to affect fear extinction consolidation. We predicted that high estradiol levels during extinction training lead to downregulation of RAS components and enhanced extinction consolidation. We show for the first time that systemic administration of AT1R antagonist losartan prior to extinction training reverses the extinction consolidation deficit found in female rats taking a hormonal contraceptive (HC), which reduces estradiol levels. We also found that female rats that receive ovariectomy (OVX) surgery have a deficit in extinction consolidation compared to sham-operated proestrus females, and that systemic treatment with losartan prior to extinction training rescues the deficit in OVX females. Finally, we explore potential mechanisms for how estradiol is regulating the RAS to affect fear extinction consolidation. While differences in RAS components have been extensively studied in OVX females, no studies have examined how HC treatment affects RAS components or how AT1R levels differ between males and females in the brain. We found that OVX females have increased AT1R ligand binding compared to intact proestrus females in the pituitary gland and ventral subiculum. We also found that HC-treated females have increased circulating angiotensin II (Ang II) peptide levels compared to proestrus females. Our findings have significant clinical implications, suggesting that patients with anxiety disorders such as PTSD should take an AT1R antagonist, especially if they have low estradiol levels, prior to an exposure therapy session to improve treatment outcome.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
17 November 2017 |
| Date Type: |
Publication |
| Defense Date: |
29 August 2017 |
| Approval Date: |
17 November 2017 |
| Submission Date: |
17 November 2017 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
164 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
ESTROGEN;
ANGIOTENSIN II TYPE I RECEPTORS;
FEAR EXTINCTION CONSOLIDATION;
FEMALES;
LOSARTAN;
CUED FEAR CONDITIONING |
| Date Deposited: |
17 Nov 2017 14:17 |
| Last Modified: |
17 Nov 2018 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/33376 |
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