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. Intermittent access (IntA) to fentanyl induces a robust “addiction‐like” state that is orexin‐dependent. Addiction behaviors induced by IntA to fentanyl are reversed by antagonism of the orexin‐1 receptor and rats given IntA to fentanyl exhibit 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.