Testing the effect of the non-selective opioid PPL-138 in a model of alcohol relapse in the context of PTSD.

Alcohol use disorder (AUD) is a frequent comorbidity in patients suffering from post-traumatic stress disorder (PTSD). Few therapeutic options are available for the individual disorders, and there are currently no drugs specifically shown to treat AUD in patients with comorbid PTSD. As PTSD has been associated with dysregulation of the brain's opioid system, our study aimed to examine the effects of a non-selective opioid compound, PPL-138, for use in co-morbid PTSD and AUD. Female and male Sprague-Dawley rats were trained to respond for alcohol in operant chambers. Following extinction, alcohol-seeking behavior was reinstated by cues previously associated with alcohol availability. All rats underwent Single Prolonged Stress (SPS) to induce PTSD-like manifestations, except for a male and female untraumatized group. Afterward, the anxiety-like behavior of all individual rats was assessed, and a second cue-induced reinstatement was conducted. Following subcutaneous PPL-138 testing (0.0, 0.1, 0.3, 1.0 mg/kg), female, but not male rats, who had escalated alcohol-seeking behavior after SPS, showed a reduction in their responses. Additionally, PPL-138 attenuated reinstatement in the subset of female rats that exhibited anxiety-like behavior. PPL-138 increased alcohol seeking in non-traumatized male rats, while leaving alcohol seeking of non-traumatized female rats unaltered. These results support the efficacy of pharmacological modulation of the opioid system in reducing both traumatic-like stress-induced escalation of alcohol-seeking behavior and cue-induced relapse associated with heightened anxiety, specifically in female rats. Classifying individuals based on traumatic stress-induced changes in alcohol-seeking behavior may provide a valuable model for evaluating pharmacological treatments for PTSD and AUD comorbidity.