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

被引:413
作者
Boutrel, B
Kenny, PJ
Specio, SE
Martin-Fardon, R
Markou, A
Koob, GF
de Lecea, L
机构
[1] Univ Lausanne, CHUV, Dept Psychiat, Ctr Psychiat Neurosci, CH-1008 Prilly, Switzerland
[2] Univ Lausanne, CHUV, Dept Psychiat, Serv Univ Psychiat Enfant & Adolescent, CH-1008 Prilly, Switzerland
[3] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA
[4] Scripps Res Inst, Dept Mol & Integrat Neurosci, La Jolla, CA 92037 USA
关键词
addiction; orexin; relapse; reward; intracranial self-stimulation;
D O I
10.1073/pnas.0507480102
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 SB334867 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.
引用
收藏
页码:19168 / 19173
页数:6
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