Hypocretin/orexin deficiency decreases cocaine abuse liability

Nadia Steiner, Clara Rossetti, Takeshi Sakurai, Masashi Yanagisawa, Luis de Lecea, Pierre J. Magistretti, Olivier Halfon, Benjamin Boutrel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Compelling evidence indicates that hypocretin/orexin signaling regulates arousal, stress and reward-seeking behaviors. However, most studies on drug reward-related processes have so far described the effects of pharmacological blockers disrupting hypocretin/orexin transmission. We report here an extensive study on cocaine-related behaviors in hypocretin/orexin-deficient mice (KO) and their heterozygous (HET) and wildtype (WT) littermates. We evaluated behavioral sensitization following repeated administrations and preference for an environment repeatedly paired with cocaine injections (15 mg/kg). Mice were also trained to self-administer cocaine (0.5–1.5 mg/kg/infusion). Our observations show that whereas all mice exhibited quite similar responses to acute administration of cocaine, only Hcrt KO mice exhibited reduced cocaine-seeking behaviors following a period of abstinence or extinction, and reduced cocaine incubation craving. Further, if the present findings confirm that Hcrt deficient mice may display a hypoactive phenotype, possibly linked to a reduced alertness concomitant to a decreased exploration of their environment, hypocretin/orexin defiency did not cause any attentional deficit. We thus report that innate disruption of hypocretin/orexin signaling moderately alters cocaine reward but significantly reduces long-term affective dependence that may explain the lack of relapse for cocaine seeking seen in Hcrt KO mice. Overall, with blunted cocaine intake at the highest concentration and reduced responsiveness to cocaine cues after prolonged abstinence, our findings suggest that hypocretin deficient mice may display signs of resilience to cocaine addiction.

Original languageEnglish (US)
Pages (from-to)395-403
Number of pages9
StatePublished - May 1 2018


  • Cocaine
  • Hypocretin
  • Motivation
  • Orexin
  • Relapse
  • Saccharine

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience


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