Oxytocin attenuates yohimbine-induced responding for oral oxycodone under a progressive ratio schedule in male and female rats.

Opioid Use Disorder (OUD) has become an epidemic in the United States, with oxycodone (OXY) being one of the most widely misused opioids. Stress plays a key role in triggering opioid use, which can lead to addiction and relapse, underscoring the urgent need for effective therapeutic interventions. Recent studies suggest that the neuropeptide oxytocin (OXT) may reduce addiction-related behaviors and possess anxiolytic properties. The present study investigates the effect of peripheral administration of OXT on attenuating stress-induced motivation to seek oral OXY, as measured by progressive ratio (PR) responding in both male and female rats. Animals were first trained in an operant conditioning paradigm to orally self-administer a sucrose solution by pressing an active lever for access to the solution. As responding stabilized, subjects were switched to an OXY-sucrose solution, with sucrose concentration reduced overtime, until subjects were self-administering oral OXY alone. To test the effect of stress on OXY responding the pharmacological stressor, yohimbine (YOH), was administered prior to a progressive ratio test in which animals were required to produce increasingly higher responses to receive a single exposure to OXY. Through a within subjects design, when OXT was concurrently administered, this YOH-induced enhancement of OXY reward strength was attenuated in both male and female rats. These results suggest that OXT may serve as a potential therapeutic remedy to mitigate the deleterious effects of stress on OXY addiction in both sexes.