The opioid partial agonist PPL‐138 reduces alcohol self‐administration in rats susceptible to post‐traumatic stress disorder

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BACKGROUND AND PURPOSE: Post-traumatic stress disorder (PTSD) is a significant challenge in the military population and civilians exposed to danger and violence. Alcohol use disorder (AUD) and pain are common PTSD comorbidities, with a higher incidence in PTSD patients than the general population. Approved pharmacotherapies for these disorders are often ineffective and adverse effect potential limits use. No current drugs address both PTSD and alcohol use disorder. This study examines whether the opioid partial agonist PPL-138 (BU10038) alleviates preclinical behaviours associated with PTSD such as anxiety, pain and comorbid alcohol use. EXPERIMENTAL APPROACH: The single prolonged stress (SPS) model induced PTSD-like phenotypes in male and female Sprague-Dawley rats. As PTSD afflicts only a subset of humans exposed to trauma, the effect of PPL-138 on alcohol self-administration was tested in SPS susceptible and resilient rat populations (defined by anxiety phenotype and escalation of alcohol-related responses). KEY RESULTS: PPL-138 effectively reduces anxiety-like behaviour, tactile allodynia and thermal hyperalgesia induced by SPS. It also decreases escalated alcohol consumption in male rats exhibiting comorbid anxiety-like behaviour, leaving alcohol intake unaltered in non-anxious phenotypes or in rats not exposed to traumatic-like stress. The compound has a similar effect in female rats, as it reduces alcohol self-administration selectively in anxious female rats. CONCLUSIONS AND IMPLICATIONS: Results support the efficacy of PPL-138 to attenuate behavioural traits attributable to PTSD and alcohol consumption associated with elevated anxiety in an AUD-PTSD population.

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