Post-traumatic stress disorder (PTSD), a trauma- and stressor-related disorder, is a condition that can develop in response to life-threatening situations. According to the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5), a diagnosis of PTSD necessitates exposure to a life-threatening event, intrusive recollections, avoidance of associated stimuli, hyperarousal, and a significant social impairment. All of these symptoms must persist for at least 30 days and not be due to illness, medication, or substance abuse. To date, no definitive diagnostic biomarkers have been identified for PTSD. Recent research, however, points toward physiological abnormalities in the brain, hypothalamic-pituitary-adrenal (HPA) axis, and immune system that may be partially responsible. Many chronic conditions such as hypertension, heart failure, and metabolic syndrome perpetuate in a state of increased inflammation and oxidative stress, exacerbating their pathophysiology. In many psychiatric conditions such as depression and anxiety disorders, neurotransmitter modulation may play a critical role in their pathogenesis. Based upon the literature and work from our laboratory, we hypothesized that similar pathophysiological mechanisms may play a role in PTSD development. We tested our theory by creating a PTSD-like syndrome in rats with the use of a predator exposure/psychosocial stress animal model. We then conducted a series of in vivo and ex vivo experiments in an attempt to discover the roles of inflammation, oxidative stress, and neurotransmitter modulation in PTSD development. First, we evaluated inflammation and oxidative stress in the brain, adrenal glands, and blood in response to the predator exposure model. We then analyzed neurotransmitter modulation in the hippocampus and prefrontal cortex. Next, we investigated the anti-inflammatory and neuromodulating effects of the histone deacetylase inhibitor (HDACi) valproic acid (VA) on inflammation/oxidative stress and neurotransmitters. Finally, we employed the selective-serotonin reuptake inhibitor (SSRI) sertraline to ascertain why SSRIs have historically been ineffective in treating PTSD. Taken together, our findings indicate inflammation, oxidative stress, and aberrant neurotransmitter profiles may play a significant role in PTSD development and progression. In addition, VA may prove to be a legitimate pharmacologic alternative in PTSD treatment, as SSRIs may increase the noradrenergic response and actually exacerbate anxiety in a clinical setting.
| Identifer | oai:union.ndltd.org:LSU/oai:etd.lsu.edu:etd-06302014-150004 |
| Date | 09 July 2014 |
| Creators | Wilson, Carl Brad |
| Contributors | Francis, Joseph, Baker, David, Strain, George, Williams, Cathleen, Harre, Joseph, Teruyama, Ryoichi |
| Publisher | LSU |
| Source Sets | Louisiana State University |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lsu.edu/docs/available/etd-06302014-150004/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached herein a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to LSU or its agents the non-exclusive license to archive and make accessible, under the conditions specified below and in appropriate University policies, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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