Progesterone decreases opioid seeking in a rat model of opioid use disorder

Background: Recent evidence suggests that intensity of withdrawal symptoms is a predictor of relapse to opioid use in women but not in men. Additionally, relapse risk is attenuated during the luteal phase of the menstrual cycle, compared to the follicular phase, suggesting that progesterone may have clinical utility for decreasing relapse risk among people with opioid use disorder (OUD). We investigated this possibility in female rats using a rat model of OUD.

Methods: In this study, female rats were initially trained to intravenously self-administer oxycodone in daily 1-hour sessions for 4 days. Rats were then shifted to extended access sessions (6 hr/day) daily for 10 days. Estrous cycle stages were monitored via daily vaginal lavage. The morning after the 10th extended access self-administration session, rats were injected s.c. with either vehicle (n = 7) or 2 mg/kg progesterone (n = 10). Thirty minutes later, rats were tested for cue-induced oxycodone seeking for 30 minutes.

Results: All rats acquired self-administration behavior. Rats in both treatment groups significantly escalated their oxycodone intake (F1.764, 26.47 = 38.89; p < 0.0001) and responding for oxycodone (F1.73, 25.95 = 18.09; p < 0.0001) over the 10 days of extended access to self-administration. However, rats that were treated with progesterone had significantly fewer active lever presses during the cue-induced oxycodone seeking test than rats that were treated with vehicle (t15 = 2.27; p = 0.038). Conclusions: These data suggest that progesterone can reduce craving for oxycodone during acute abstinence. These data could have important implications for relapse prevention and/or treatment of OUD in women.