Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior.
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.
Boutrel
Benjamin
B
Center 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
Kenny
Paul J
PJ
Specio
Sheila E
SE
Martin-Fardon
Rémi
R
Markou
Athina
A
Koob
George F
GF
de Lecea
Luis
L
D000704:Analysis of Variance; D000818:Animals; D016739:Behavior, Addictive; D001583:Benzoxazoles / Q000494:pharmacology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003042:Cocaine / Q000378:metabolism*; D019970:Cocaine-Related Disorders / Q000378:metabolism / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D015233:Models, Statistical; D009287:Naphthyridines; D009479:Neuropeptides / Q000737:chemistry / Q000494:pharmacology*; D000068797:Orexins; D051381:Rats; D017208:Rats, Wistar; D012201:Reward; D012646:Self Administration; D013997:Time Factors; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D000068797:Orexins; D014508:Urea; D003042:Cocaine