Graduation Year

2008

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Psychology

Major Professor

David Diamond, Ph.D.

Committee Member

Paula Bickford, Ph.D.

Committee Member

Cheryl Kirstein, Ph.D.

Committee Member

Edward Levine, Ph.D.

Committee Member

Kristen Salomon, Ph.D.

Keywords

PTSD, glucocorticoids, hippocampus, amygdala, antidepressants

Abstract

Post-traumatic stress disorder (PTSD) is a debilitating mental illness that results from exposure to intense, life-threatening trauma. Some of the symptoms of PTSD include intrusive flashback memories, persistent anxiety, hyperarousal and cognitive impairments. The finding of reduced basal glucocorticoid levels, as well as a greater suppression of glucocorticoid levels following dexamethasone administration, has also been commonly observed in people with PTSD. Our laboratory has developed an animal model of PTSD which utilizes chronic psychosocial stress, composed of unavoidable predator exposure and daily social instability, to produce changes in rat physiology and behavior that are comparable to the symptoms observed in PTSD patients. The present set of experiments was therefore designed to 1) test the hypothesis that our animal model of PTSD would produce abnormalities in glucocorticoid levels that are comparable to those observed in people with PTSD, 2) examine the ability of antidepressant and anxiolytic agents to ameliorate the PTSD-like physiological and behavioral symptoms induced by our paradigm and 3) ascertain how long the physiological and behavioral effects of our stress regimen could be maintained.

The experimental findings revealed that our animal model of PTSD produces a reduction in basal glucocorticoid levels and increased negative feedback sensitivity to the synthetic glucocorticoid, dexamethasone. In addition, chronic prophylactic administration of amitriptyline (tricyclic antidepressant) and clonidine (α2-adrenergic receptor agonist) prevented a subset of the effects of chronic stress on rat physiology and behavior, but tianeptine (antidepressant) was the only drug to block the effects of chronic stress on all physiological and behavioral measures. The final experiment indicated that only a subset of the effects of chronic stress on rat physiology and behavior could be observed 4 months following the initiation of chronic stress, suggesting that some of the effects of our animal model diminish over time. Together, these findings further validate our animal model of PTSD and may provide insight into the mechanisms underlying trauma-induced changes in brain and behavior. They also provide guidance for pharmacotherapeutic approaches in the treatment of individuals suffering from PTSD.

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