Jennifer E. Fragale^a, Morgan H. James^a, Jorge A. Avila^a, Andrea M. Spaeth^b, R. Nisha Aurora^c, Daniel Langleben^d, Gary Aston-Jones^a

^a Brain Health Institute, Rutgers Biomedical Health Sciences, Rutgers University, Piscataway, NJ, USA; 
^b Department of Kinesiology and Health, Rutgers University, New Brunswick, NJ, USA; 
^c Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA; 
^d Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

© 2021 The Author(s)
Published by S. Karger AG, Basel

• Chapter 10 graphical abstract

Significant sleep impairments often accompany substance use disorders (SUDs). Sleep disturbances in SUD patients are associated with poor clinical outcomes and treatment adherence, emphasizing the importance of normalizing sleep when treating SUDs. Orexins (hypocretins) are neuropeptides exclusively produced by neurons in the posterior hypothalamus that regulate various behavioral and physiological processes, including sleep-wakefulness and motivated drug taking. Given its dual role in sleep and addiction, the orexin system represents a promising therapeutic target for treating SUDs and their comorbid sleep deficits. Here, we review the literature on the role of the orexin system in sleep and drug addiction and discuss the therapeutic potential of orexin receptor antagonists for SUDs. We argue that orexin receptor antagonists may be effective therapeutics for treating addiction because they target orexin’s regulation of sleep (top-down) and motivation (bottom-up) pathways.

• Sleep impairments are comorbid in individuals with substance abuse disorders.
• There is a positive feedback loop where drug intake causes increased orexin signaling, which in turn increases motivation for drug and impairs sleep and executive function, causing further drug intake.
• Orexin receptor antagonists can break the cycle between drug use, motivation and sleep deficits.

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