Role for Hypocretin in Mediating Stress-Induced Reinstatement of Cocaine-Seeking Behavior

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 52; pp. 19168 - 19173
• Main Authors: Benjamin Boutrel, Paul J. Kenny, Sheila E. Specio, Rémi Martin-Fardon, Markou, Athina, Koob, George F., de Lecea, Luis
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 27.12.2005; National Acad Sciences
• Subjects: Addictions; Analysis of Variance; Animals; Behavior, Addictive; Behavioral neuroscience; Benzoxazoles - pharmacology; Biological Sciences; Brain; Brain - metabolism; Brain - pathology; Cocaine; Cocaine - metabolism; Cocaine-Related Disorders - metabolism; Cocaine-Related Disorders - pathology; Dosage; Dose-Response Relationship, Drug; Drug seeking behavior; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - pharmacology; Male; Models, Statistical; Neurology; Neurons; Neuropeptides - chemistry; Neuropeptides - pharmacology; Orexins; Peptides; Rats; Rats, Wistar; Receptors; Relapse; Reward; Self Administration; Statistical analysis; Time Factors; Urea - analogs & derivatives; Urea - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0507480102

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.