Social stress cue exposure heightens opioid preference and locus coeruleus neuroimmune activity in female rats

Stress exposure is often a precipitating factor underlying drug-seeking behavior that can lead to the establishment of comorbid posttraumatic stress disorder and substance use disorder (SUD) in clinical populations. The vicarious witness stress (WS) model is a potent ethologically relevant stressor that imparts many of its deleterious effects through heightened neuroimmune signaling in key stress sensitive brain regions. The present set of studies were designed to determine the impact of this psychosocial stressor on oxycodone place preference and central immune activity in female rats. In this way, we aim to better understand the neural correlates of stress-induced drug seeking in an effort to establish novel treatment targets for stress-related posttraumatic stress disorder/SUD. Female Sprague-Dawley rats were exposed to WS or nonstress control conditions prior to training for conditioned place preference with 3.0 mg/kg oxycodone. Following conditioned place preference training, rats with a history of stress were either exposed to the WS cues or left undisturbed and compared to controls for oxycodone place preference. Acute exposure to the WS cues led to the highest amount of time spent in the drug-paired compartment and this stress-induced augmentation of opioid preference was accompanied by significant increases in proinflammatory cytokines in the locus coeruleus. Taken together, these experiments established a comorbid model of stress and drug preference in female rats and have begun to identify potential brain regions that could be targeted to prevent stress-related sensitization to SUDs in females. SIGNIFICANCE STATEMENT: These studies offer insights into neuroimmune targets for the prevention of stress-induced opioid seeking with the overall goal of testing translationally relevant pharmacotherapies to prevent stress-sensitized drug-seeking responses in females.