title: Hypocretin/Orexin regulation of dopamine signaling and cocaine self-administration is mediated predominantly by hypocretin receptor 1.
abstract: Extensive evidence suggests that the hypocretins/orexins influence cocaine reinforcement and dopamine signaling via actions at hypocretin receptor 1. By comparison, the involvement of hypocretin receptor 2 in reward and reinforcement processes has received relatively little attention. Thus, although there is some evidence that hypocretin receptor 2 regulates intake of some drugs of abuse, it is currently unclear to what extent hypocretin receptor 2 participates in the regulation of dopamine signaling or cocaine self-administration, particularly under high effort conditions. To address this, we examined the effects of hypocretin receptor 1, and/or hypocretin receptor 2 blockade on dopamine signaling and cocaine reinforcement. We used in vivo fast scan cyclic voltammetry to test the effects of hypocretin antagonists on dopamine signaling in the nucleus accumbens core and a progressive ratio schedule to examine the effects of these antagonists on cocaine self-administration. Results demonstrate that blockade of either hypocretin receptor 1 or both hypocretin receptor 1 and 2 significantly reduces the effects of cocaine on dopamine signaling and decreases the motivation to take cocaine. In contrast, blockade of hypocretin receptor 2 alone had no significant effects on dopamine signaling or self-administration. These findings suggest a differential involvement of the two hypocretin receptors, with hypocretin receptor 1 appearing to be more involved than hypocretin receptor 2 in the regulation of dopamine signaling and cocaine self-administration. When considered with the existing literature, these data support the hypothesis that hypocretins exert a permissive influence on dopamine signaling and motivated behavior via preferential actions on hypocretin receptor 1.
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine , Philadelphia, Pennsylvania 19129, United States.
authors.forename: Courtney D
authors.initials: CD
authors.lastname: Prince
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Rau
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Yorgason
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: España
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D055664:Electrochemical Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D009287:Naphthyridines; D009479:Neuropeptides / Q000378:metabolism*; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000378:metabolism*; D000068797:Orexins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D015398:Signal Transduction / Q000187:drug effects*; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D018765:Dopamine Uptake Inhibitors; C578627:Hcrtr1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D000068797:Orexins; D014508:Urea; D003042:Cocaine; D004298:Dopamine
keywords: Addiction; drug abuse; fast scan cyclic voltammetry; motivation; reward