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The Journal of Neuroscience, April 1, 2009, 29(13):4155-4161; doi:10.1523/JNEUROSCI.5256-08.2009

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Behavioral/Systems/Cognitive
Neuropeptide S Reinstates Cocaine-Seeking Behavior and Increases Locomotor Activity through Corticotropin-Releasing Factor Receptor 1 in Mice

Covadonga Pañeda,¹ Salvador Huitron-Resendiz,¹ Laura M. Frago,³ Julie A. Chowen,³ Roberto Picetti,⁴ Luis de Lecea,^1,2 and Amanda J. Roberts¹

Departments of ¹Molecular and Integrative Neurosciences and ²Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, ³Hospital Universitario del Niño Jesús, Universidad Autónoma de Madrid, 28006 Madrid, Spain, and ⁴Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, New York 10065

Correspondence should be addressed to either of the following: Covadonga Pañeda, Instituto de Investigaciones Biomédicas, c/Arturo Duperier 4, 28029 Madrid, Spain, Email: cpaneda{at}iib.uam.es; or Amanda J. Roberts, Department of Molecular and Integrative Neurosciences, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, E-mail: Email: aroberts{at}scripps.edu

Neuropeptide S (NPS) is a recently discovered neuropeptide that increases arousal and wakefulness while decreasing anxiety-like behavior. Here, we used a self-administration paradigm to demonstrate that intracerebroventricular infusion of NPS reinstates extinguished cocaine-seeking behavior in a dose-dependent manner in mice. The highest dose of NPS (0.45 nM) increased active lever pressing in the absence of cocaine to levels that were equivalent to those observed during self-administration. In addition, we examined the role of the corticotropin-releasing factor receptor 1 (CRF₁) in this behavior as well as locomotor stimulation and anxiolysis. CRF₁ knock-out mice did not respond to either the locomotor stimulant or cocaine reinstatement effects of NPS, but still responded to its anxiolytic effect. The CRF₁ antagonist antalarmin also blocked the increase in active lever responding in the reinstatement model and the locomotor activating properties of NPS without affecting its anxiolytic actions. Our results suggest that NPS receptors may be an important target for drug abuse research and treatment and that CRF₁ mediates the cocaine-seeking and locomotor stimulant effects of NPS, but not its effects on anxiety-like behavior.

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Received Oct. 31, 2008; revised Feb. 25, 2009; accepted Feb. 25, 2009.

Correspondence should be addressed to either of the following: Covadonga Pañeda, Instituto de Investigaciones Biomédicas, c/Arturo Duperier 4, 28029 Madrid, Spain, Email: cpaneda{at}iib.uam.es; or Amanda J. Roberts, Department of Molecular and Integrative Neurosciences, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, E-mail: Email: aroberts{at}scripps.edu

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