title: Blockade of hypocretin receptor-1 preferentially prevents cocaine seeking: comparison with natural reward seeking.
abstract: Hypothalamic orexin/hypocretin (Orx/Hcrt) peptides participate in the regulation of a wide range of physiological processes and are recruited by drugs of abuse. To advance our understanding of the potential of the Orx/Hcrt receptor-1 (Hcrt-r1) as a treatment target for cocaine addiction, the effect of SB334867 [N-(2-methyl-6-benzoxazolyl)-N'-1,5-n-aphthyridin-4-yl urea], a specific Hcrt-r1 antagonist, on reinstatement elicited by cocaine-associated stimuli versus stimuli associated with a highly palatable conventional reinforcer [sweetened condensed milk (SCM)] was tested. Two separate groups of male Wistar rats were trained to associate a discriminative stimulus (S⁺) with the response-contingent availability of cocaine (0.25 mg/0.1 ml/infusion) or SCM [2/1 (v/v)] and subjected to reinstatement tests following extinction of cocaine-reinforced or SCM-reinforced behavior, during which the reinforcers and S⁺ were withheld. Following extinction, presentation of the cocaine or SCM S⁺ produced comparable recovery of responding. Hcrt-r1 blockade by SB334867 (1-10 mg/kg, intraperitoneal) dose-dependently and selectively reversed conditioned reinstatement induced by cocaine-related stimuli, without interfering with reward seeking produced by the same stimulus when conditioned to SCM. The findings suggest an important role for Hcrt-r1 in appetitive behavior controlled by reward-related stimuli with selectivity for cocaine seeking and identify Hcrt-r1 as a potential treatment target for cocaine relapse prevention.
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Rémi
authors.initials: R
authors.lastname: Martin-Fardon
authors.forename: Friedbert
authors.initials: F
authors.lastname: Weiss
mesh_terms: D000704:Analysis of Variance; D000779:Anesthetics, Local / Q000008:administration & dosage*; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000503:physiopathology* / Q000523:psychology; D003216:Conditioning, Operant / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology*; D005108:Extinction, Psychological / Q000187:drug effects; D008297:Male; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012201:Reward; D012646:Self Administration; D013549:Sweetening Agents / Q000008:administration & dosage; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D000779:Anesthetics, Local; D001583:Benzoxazoles; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D013549:Sweetening Agents; D014508:Urea; D003042:Cocaine