Iboga alkaloid congeners attenuate fentanyl seeking during prolonged abstinence after vapor self-administration

Background. The prevalence of opioid use disorder (OUD) has reached epidemic proportions with a record-breaking number of overdose deaths. Over 70% of the overdose deaths are caused by synthetic opioids, including fentanyl. Fentanyl is commonly administered intravenously or by inhalation (smoking/vaping), which results in rapid drug bioavailability in the brain. There is an urgent need to identify novel pharmacotherapies to treat OUD. There is increasing evidence to support the use of ibogaine analogs, also known as iboga alkaloids, to treat OUD and other psychiatric illnesses. In preclinical models, iboga alkaloids, such as 18-methoxcoronaridine (18-MC), have been shown to decrease opioid self-administration and seeking and induce antidepressant and anxiolytic effects. To our knowledge, there is no published research examining the effects of catharanthine (Cath) on drug seeking behaviors. Here we used a preclinical fentanyl vapor self-administration model to study the anti-addictive effects of two iboga alkaloid congeners, 18-MC and Cath.

Methods. Male and female C57BL/6 mice were trained to self-administer vaporized fentanyl (5 mg/mL) or vehicle in air-tight operant chambers for 10 1-hour sessions. Mice learned to self-administer vapor reward with 3-second vapor deliveries for the first 3 sessions of training, which was then reduced to 1.5-second vapor deliveries for the remaining 7 sessions. After training, mice were returned to their home cages for a forced abstinence period. Cue-induced drug seeking tests were conducted on abstinence day (AD) 20 and AD25. Cue-induced drug seeking tests were conducted using a crossover design where half of subjects were injected (i.p.) with iboga treatment (18-MC or Cath), while the other half received vehicle (ddH2O), on AD20 1 hour before seeking tests. On AD25, subjects received the opposite treatment compared to AD20.

Results. We found that both 18-MC and Cath significantly reduced fentanyl seeking during prolonged abstinence in both males and females with no effect on mice that had previously self-administered vehicle vapor.

Conclusion. In this study, we report that both 18-MC and Cath decrease fentanyl seeking during prolonged abstinence in both males and females. These results add evidence to the existing literature that iboga alkaloids may be a promising class of compounds for novel pharmacotherapeutic treatment of OUD.