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Access Type

WSU Access

Date of Award

January 2022

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Psychiatry and Behavioral Neurosciences

First Advisor

Christine A. Rabinak

Second Advisor

Mark K. Greenwald

Abstract

Posttraumatic stress disorder (PTSD) can occur after exposure to a traumatic event (e.g., assault, car crash), leaving individuals with debilitating symptoms. Our first-line treatments for PTSD include exposure-based therapies that target the two primary deficits of PTSD: inability to suppress inappropriate fear responses and avoidance behaviors. While effective, over one-quarter of patients do not see a significant decrease in symptoms or relapse after exposure therapy. Thus far, much work identifies pharmacological adjuncts for exposure therapy by testing its effects on neurobehavioral signatures of extinction memory retention (i.e., suppression of an inappropriate fear responses). Limited work determines the neurobehavioral effects of avoidance behaviors in PTSD, preventing us from identifying a pharmacological adjunct for improving both deficits of the disorder. There is promising evidence that the endocannabinoid (eCB) system may be an effective target to improve these dysfunctions. The eCB system is responsible for our response and recovery to fear and stress, is essential for extinction memory retention, and regulates approach-avoidance behaviors. Thus, this dissertation aimed to identify and test a novel, eCB-based intervention [delta-9-tetrahydrocannbinol (THC)] to improve both extinction memory retention and avoidance behaviors in those with PTSD. We first determined the effect of trauma-related avoidance behaviors on indices of fear and a corticolimbic-striatal network in trauma-exposed adults with and without PTSD. We found no effect of avoidance behaviors on these measures. Next, we determined the dose-dependent effect of THC on fear indices and corticolimbic activation during extinction memory retention test in adults with PTSD; low doses of THC (5 or 7.5 mg) lessened fear responses compared to placebo or a high dose (10 mg); 5 mg of THC also reduced amygdala activation during extinction recall, compared to PBO. Finally, we tested the dose-dependent effect of THC on avoidance-related fear indices and corticolimbic-striatal functional connectivity in adults with and without PTSD; THC did not dose-dependently impact fear indices or functional connectivity of a corticolimbic-striatal network in those with low or high avoidance behaviors. These data demonstrate that eCB modulation may improve extinction memory retention and suggests that trauma-related avoidance behaviors may not hinder success of eCB-based treatments in those with PTSD.

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