A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?

  • Morgan H. James
  • Stephen V. Mahler
  • David E. Moorman
  • Gary Aston-JonesEmail author
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 33)


One decade ago, our laboratory provided the first direct evidence linking orexin/hypocretin signaling with drug seeking by showing that activation of these neurons promotes conditioned morphine-seeking behavior. In the years since, contributions from many investigators have revealed roles for orexins in addiction for all drugs of abuse tested, but only under select circumstances. We recently proposed that orexins play a fundamentally unified role in coordinating “motivational activation” under numerous behavioral conditions, and here we unpack this hypothesis as it applies to drug addiction. We describe evidence collected over the past 10 years that elaborates the role of orexin in drug seeking under circumstances where high levels of effort are required to obtain the drug, or when motivation for drug reward is augmented by the presence of external stimuli like drug-associated cues/contexts or stressors. Evidence from studies using traditional self-administration and reinstatement models, as well as behavioral economic analyses of drug demand elasticity, clearly delineates a role for orexin in modulating motivational, rather than the primary reinforcing aspects of drug reward. We also discuss the anatomical interconnectedness of the orexin system with wider motivation and reward circuits, with a particular focus on how orexin modulates prefrontal and other glutamatergic inputs onto ventral tegmental area dopamine neurons. Last, we look ahead to the next decade of the research in this area, highlighting the recent FDA approval of the dual orexin receptor antagonist suvorexant (Belsomra®) for the treatment of insomnia as a promising sign of the potential clinical utility of orexin-based therapies for the treatment of addiction.


Addiction Alcohol Behavioral economics Cocaine Dopamine Drugs of abuse Glutamate Heroin Hypocretin Motivation Orexin Reward VTA 



This work is supported by an NHMRC CJ Martin Fellowship (1072706) to M.H.J., and PHS grants R00 DA035251 to SVM, and R01 DA006214 to GAJ. Support for DEM: R21 DA041674.


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Authors and Affiliations

  • Morgan H. James
    • 1
    • 2
  • Stephen V. Mahler
    • 3
  • David E. Moorman
    • 4
  • Gary Aston-Jones
    • 1
    Email author
  1. 1.Brain Health InstituteRutgers University/Rutgers Biomedical and Health SciencesPiscatawayUSA
  2. 2.Florey Institute of Neuroscience and Mental HealthUniversity of MelbourneParkvilleAustralia
  3. 3.Department of Neurobiology and BehaviorUniversity of California, IrvineIrvineUSA
  4. 4.Department of Psychological and Brain Sciences & Neuroscience and Behavior Graduate ProgramUniversity of Massachusetts AmherstAmherstUSA

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