biostudies-literatureMehr JBNIDA NIH HHSNational Institute on Drug Abuse852-855https://www.ebi.ac.uk/biostudies/studies/S-EPMC8772282biostudies-literatureUnknown44(11)Although originally implicated in appetite and sleep/wakefulness, the hypothalamic orexin (hypocretin) system has now been demonstrably linked with motivated behavior. This highly plastic system responds to reward-associated environmental stimuli and becomes pathologically overactive in addicted states. Here, we provide a brief overview of the roles of the orexin system in reward-seeking and addiction, as well as potential therapeutic opportunities for substance use disorders based on normalizing orexin function.Trends in neurosciencesOrexin (hypocretin) and addiction.PMC8772282R00 045765R00 DA045765James MHMehr JBBilotti MMfalseOrexin (hypocretin) and addiction.Although originally implicated in appetite and sleep/wakefulness, the hypothalamic orexin (hypocretin) system has now been demonstrably linked with motivated behavior. This highly plastic system responds to reward-associated environmental stimuli and becomes pathologically overactive in addicted states. Here, we provide a brief overview of the roles of the orexin system in reward-seeking and addiction, as well as potential therapeutic opportunities for substance use disorders based on normalizing orexin function.2021-01-01T00:00:00Z2021 Nov2025-04-04T22:33:49.532Z2025-02-19T03:24:04.348ZS-EPMC87722823464208610.1016/j.tins.2021.09.002