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

Academic Article
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Overview

authors

  • Boutrel, B.
  • Kenny, Paul
  • Specio, S. E.
  • Martin-Fardon, Remi
  • Markou, A.
  • Koob, George
  • de Lecea, L.

publication date

  • December 2005

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

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.

subject areas

  • Analysis of Variance
  • Animals
  • Behavior, Addictive
  • Benzoxazoles
  • Brain
  • Cocaine
  • Cocaine-Related Disorders
  • Dose-Response Relationship, Drug
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Models, Statistical
  • Neuropeptides
  • Orexins
  • Rats
  • Rats, Wistar
  • Reward
  • Self Administration
  • Time Factors
  • Urea
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Research

keywords

  • addiction
  • intracranial self-stimulation
  • orexin
  • relapse
  • reward
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Identity

PubMed Central ID

  • PMC1323172

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0507480102

PubMed ID

  • 16357203
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Additional Document Info

start page

  • 19168

end page

  • 19173

volume

  • 102

issue

  • 52

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