title: Selective orexin 2 receptor antagonism blocks cue-induced reinstatement, but not nicotine self-administration or nicotine-induced reinstatement.
abstract: The orexinergic system has been implicated in a number of behaviors, including reward and incentive motivation. Orexin 1 receptor antagonism has been reported to reduce drug self-administration, conditioned place preference, and reinstatement in rodents, but the role of the orexin 2 receptor is unclear. Here we evaluated the impact of the novel and selective orexin 2 receptor antagonist, 2-SORA 18, on motivation for nicotine as measured by responding on a progressive ratio schedule, as well as cue-induced reinstatement of a response previously associated with nicotine reward, and nicotine-induced reinstatement. 2-SORA 18 demonstrated selective effects on these behaviors. Specifically, doses up to 60 mg/kg 2-SORA 18 were without significant effect on nicotine self-administration or nicotine-induced reinstatement, but doses as low as 15 mg/kg 2-SORA 18 completely blocked cue-induced reinstatement. These findings indicate that orexin 2 receptor antagonism might have utility for attenuating relapse, particularly for patients sensitive to environmental stimuli associated with drug taking.
authors.affiliation: Departments of Pharmacology, Merck & Co., Inc., West Point, PA 19486, USA. Electronic address: Jason_Uslaner@merck.com.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
authors.affiliation: Departments of Neuroscience, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.affiliation: Departments of Neuroscience, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.affiliation: Departments of Medicinal Chemistry, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Roecker
authors.affiliation: Departments of Medicinal Chemistry, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.affiliation: Departments of Neuroscience, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Pete H
authors.initials: PH
authors.lastname: Hutson
authors.affiliation: Department of Neuroscience, Neurobiology of Alcohol Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Anh D
authors.initials: AD
authors.lastname: Le
authors.affiliation: Departments of Neuroscience, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
mesh_terms: D000818:Animals; D002491:Central Nervous System Agents / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003463:Cues; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology; D004435:Eating / Q000187:drug effects / Q000502:physiology; D008297:Male; D009042:Motivation / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000378:metabolism; D020318:Rats, Long-Evans; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration; D014029:Tobacco Use Disorder / Q000503:physiopathology
chemical_list: D002491:Central Nervous System Agents; D018722:Nicotinic Agonists; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D009538:Nicotine
keywords: Addiction; Antagonist; Nicotine; Orexin; Reinstatement