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Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19168-73. Epub 2005 Dec 15.

Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior.

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  • 1Center for Psychiatric Neuroscience and Service Universitaire de Psychiatrie de l'Enfant et de l'Adolescent, Centre Hospitalier Universitaire Vaudois-Département de Psychiatrie, University of Lausanne, Prilly, Switzerland. benjamin.boutrel@chuv.ch

Abstract

Hypocretin-1 and -2 (Hcrt-1 and Hcrt-2), also referred to as orexin-A and -B, are neuropeptides synthesized by a few thousand neurons in the lateral hypothalamus. Hypocretin-containing neurons project throughout the brain, with a prominent input to basal forebrain structures involved in motivation, reward, and stress. However, the role of hypocretins in addiction-related behaviors remains largely unexplored. Here we show that intracerebroventricular infusions of Hcrt-1 lead to a dose-related reinstatement of cocaine seeking without altering cocaine intake in rats. Hcrt-1 also dramatically elevates intracranial self-stimulation thresholds, indicating that, unlike treatments with reinforcing properties such as cocaine, Hcrt-1 negatively regulates the activity of brain reward circuitries. Hypocretin-induced reinstatement of cocaine seeking was prevented by blockade of noradrenergic and corticotropin-releasing factor systems, suggesting that Hcrt-1 reinstated drug seeking through induction of a stress-like state. Consistent with this interpretation, the selective Hcrt-1 receptor antagonist SB-334867 blocked footshock-induced reinstatement of previously extinguished cocaine-seeking behavior. These findings reveal a previously unidentified role for hypocretins in driving drug seeking through activation of stress pathways in the brain.

PMID:
16357203
[PubMed - indexed for MEDLINE]
PMCID:
PMC1323172
Free PMC Article
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