Intermittent self-administration of fentanyl induces a multifaceted addiction state associated with persistent changes in the orexin system.

The orexin (hypocretin) system plays a critical role in motivated drug taking. Cocaine self-administration with the intermittent access (IntA) procedure produces a robust addiction-like state that is orexin-dependent. Here, we sought to determine the role of the orexin system in opioid addiction using IntA self-administration of fentanyl. Different groups of male rats were either given continuous access in 1-h period (short access [ShA]), 6-h period (long access [LgA]), or IntA (5 min of access separated by 25 min of no access for 6 h) to fentanyl for 14 days. IntA produced a greater escalation of fentanyl intake, increased motivation for fentanyl on a behavioral economics task, persistent drug seeking during abstinence, and stronger cue-induced reinstatement compared with rats given ShA or LgA. We found that addiction behaviors induced by IntA to fentanyl were reversed by the orexin-1 receptor antagonist SB-334867. IntA to fentanyl was also associated with a persistent increase in the number of orexin neurons. Together, these results indicate that the IntA model is a useful tool in the study of opioid addiction and that the orexin system is critical for the maintenance of addiction behaviors induced by IntA self-administration of fentanyl.