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A Novel Brain Penetrant NPS Receptor Antagonist, NCGC00185684, Blocks Alcohol-Induced ERK-Phosphorylation in the Central Amygdala and Decreases Operant Alcohol Self-Administration in Rats
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
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2013 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, no 24, 10132-10142 p.Article in journal (Refereed) Published
Abstract [en]

The Neuropeptide S receptor, a Gs/Gq-coupled GPCR expressed in brain regions involved in mediating drug reward, has recently emerged as a candidate therapeutic target in addictive disorders. Here, we describe the in vitro and in vivo pharmacology of a novel, selective and brain penetrant NPSR antagonist with nanomolar affinity for the NPSR, NCGC00185684. In vitro, NCGC00185684 shows biased antagonist properties, and preferentially blocks ERK-phosphorylation over intracellular cAMP or calcium responses to NPS. In vivo, systemic NCGC00185684 blocks alcohol-induced ERK-phosphorylation in the rat central amygdala, a region involved in regulation of alcohol intake. NCGC00185684 also decreases operant alcohol self-administration, and lowers motivation for alcohol reward as measured using progressive ratio responding. These effects are behaviorally specific, in that they are observed at doses that do not influence locomotor activity or reinstatement responding following extinction. Together, these data provide an initial validation of the NPSR as a therapeutic target in alcoholism.

Place, publisher, year, edition, pages
Society for Neuroscience , 2013. Vol. 33, no 24, 10132-10142 p.
Keyword [en]
addiction, neuropeptide S, phosphorylation
National Category
URN: urn:nbn:se:liu:diva-94652DOI: 10.1523/JNEUROSCI.4742-12.2013ISI: 000320235300028PubMedID: 23761908OAI: diva2:634181
Available from: 2013-06-28 Created: 2013-06-28 Last updated: 2013-12-13Bibliographically approved

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Thorsell, AnnikaHeilig, Markus
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