Brain Health Institute, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, New Jersey, USA.
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia.
Addict Biol. 2021 May;26(3):e12946. doi: 10.1111/adb.12946. Epub 2020 Aug 14.
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.
食欲素（下丘脑分泌素）系统在动机性药物摄取中起着关键作用。间歇性给予可卡因（IntA）会产生类似成瘾的状态，这种状态依赖于食欲素。在这里，我们试图使用芬太尼的 IntA 自我给药来确定食欲素系统在阿片类药物成瘾中的作用。不同组别的雄性大鼠连续 14 天接受芬太尼的 1 小时（短时间接触 [ShA]）、6 小时（长时间接触 [LgA]）或 IntA（5 分钟接触，25 分钟无接触，共 6 小时）接触。与给予 ShA 或 LgA 的大鼠相比，IntA 产生了更大的芬太尼摄入量增加、对芬太尼的行为经济学任务的动机增加、戒断期间持续的觅药行为以及更强的线索诱导复吸。我们发现，食欲素-1 受体拮抗剂 SB-334867 逆转了 IntA 诱导的芬太尼成瘾行为。IntA 到芬太尼也与食欲素神经元数量的持续增加有关。综上所述，这些结果表明，IntA 模型是研究阿片类药物成瘾的有用工具，并且食欲素系统对于维持 IntA 自我给予芬太尼诱导的成瘾行为至关重要。
