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Behav Brain Res. 2014 Aug 1;269:61-5. doi: 10.1016/j.bbr.2014.04.012. Epub 2014 Apr 18.

Selective orexin 2 receptor antagonism blocks cue-induced reinstatement, but not nicotine self-administration or nicotine-induced reinstatement.

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Departments of Pharmacology, Merck & Co., Inc., West Point, PA 19486, USA. Electronic address:
Departments of Neuroscience, Merck & Co., Inc., West Point, PA 19486, USA.
Departments of Medicinal Chemistry, Merck & Co., Inc., West Point, PA 19486, USA.
Department of Neuroscience, Neurobiology of Alcohol Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada.


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.


Addiction; Antagonist; Nicotine; Orexin; Reinstatement

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