Dissecting Comorbidity Between Opioid Use/Dependence and Post-Traumatic Stress Disorder

The focus of this dissertation is to explore how opioid use and dependence might promote the development and persistence post-traumatic stress disorder (PTSD). In addition to giving further insight into the etiology of PTSD, this research sheds important light on the ramifications of opioid use, whose licit and illicit use has skyrocketed in recent years. The contained experiments explore the relationship between opioid use and PTSD from a behavioral-mechanistic stance, addressing the precise cognitive processes related to fear impacted by opioid use, and moreover, begin to address the receptor systems through which opioid use potentiates fear learning. The experiments presented also begin to examine how trauma influences associative learning about drugs of abuse in order to understand one of the largest predictors of substance use disorders: trauma. Utilizing a rodent model of PTSD in conjunction with various pharmacological manipulations, it is demonstrated that chronic exposure to opioids is able to produce a lasting enhancement in the mechanisms that support fear learning. This enhancement was found to be independent of changes in pain sensitivity and anxiety, and was also shown not be a consequence of the stress of repeated withdrawal. Moreover, opioid-induced changes in fear learning were accompanied by markers of increased plasticity within the basolateral amygdala, a critical site for associative fear learning. These findings have serious implications for the medicinal and non-medicinal use of opioids, particularly given high rates of opioid prescriptions amongst those who undergo physical traumas.With respect to receptor systems, although dynorphin release and subsequent kappa receptor activation has been proposed to support increased anxiety as a consequence of drug use, kappa antagonism failed to counter opioid-induced increases in fear learning. Moreover, counter to recent research suggesting anxiolytic properties of kappa antagonism, we were unable to detect any anxiolytic efficacy of a kappa receptor antagonist. It is likely that the conditions under which dynorphin release supports anxiety are limitied, and their therapeutic efficacy must be considered in this light. Lastly, prior traumatic experience was found to robustly increase opioid sensitivity. However, counter to the initial hypothesis, trauma was unable to augment associative learning about opioids in the conditioned place preference task. This finding suggests that the potentiation of amygdala-dependent learning by trauma is restricted to aversive associations. Future research hopes to further explorer the relevance of heightened opioid sensitivity to drug-seeking behaviors