ABSTRACT Post-traumatic stress disorder (PTSD) is a debilitating disorder that develops in a subpopulation (~20-30%) of people exposed to a traumatic event. PTSD is highly comorbid with substance use disorder (SUD), with alcohol, stimulants and opioids being the most frequently abused drugs. Despite the prevalence of PTSD+SUD comorbidity, animal models of such comorbidity are lacking and are sorely needed to screen potential treatments. Here we will utilize our novel animal model of PTSD+SUD that captures several key features of PTSD+SUD comorbidity: 1) PTSD typically arises from a single trauma, 2) not all trauma-exposed individuals develop PTSD, 3) post-trauma anxiety symptoms are long-lasting, and 4) increased drug-craving and resistance to traditional interventions that reduce relapse in SUD. This model relies on exposing rodents to an ethologically-relevant “trauma” - predator scent stress (PSS). We have successfully combined the PSS model of PTSD with the extended access to cocaine self-administration to study PTSD+cocaine use disorder (CUD) in animals. The present application proposes to adapt this animal model to study the interaction between opioid use disorder (OUD) and PTSD. Our overall hypothesis is that, as we demonstrated for cocaine, stress-Susceptible rats will display greater oxycodone seeking, a possible indication of similar neurobiological underpinnings of both cocaine and opioid seeking in stress susceptible rats. We will assess opioid seeking using two models. Aim 1 will utilize demand curve analyses (increasing the “cost” to obtain intravenous oxycodone infusions over days) to calculate the essential demand for oxycodone and use regression models to assess the relationship between anxiety and oxycodone demand. This work will be done in males and females, and thus, will be the first work to assess sex differences in demand for oxycodone. We have found that stress-susceptibility results in increased cue-primed reinstatement of cocaine-seeking and impaired instrumental extinction of the response made to obtain cocaine. Aim 2 will assess if the same is true for oxycodone seeking, which would imply a common circuit or circuits mediating enhanced stress susceptibility and drug-seeking and potentially lead to pharmacotherapies for individuals with both OUD and CUD. Our rationale is that rat models that more closely model comorbidities accompanying human substance use should more accurately reproduce the underlying neuroadaptations present in humans, and should thus serve as better platforms for therapeutic discovery. As such, our central, unified hypothesis is that susceptibility to stress remodels circuits involved in drug seeking in a similar manner for cocaine and opioids. Future research proposals would interrogate neurobiological substrates and circuit(s) involved in differential oxycodone seeking. For example, we have found that mGlu5 expression in the amygdala and prefrontal cortex is increased in Resilient rats relative to...