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

Annika Thorsell, Jenica D. Tapocik, Ke Liu, Michelle Zook, Lauren Bell, Meghan Flanigan, Samarjit Patnaik, Juan Marugan, Ruslan Damadzic, Seameen J. Dehdashti, Melanie L. Schwandt, Noel Southall, Christopher P. Austin, Robert Eskay, Roberto Ciccocioppo, Wei Zheng, Markus Heilig

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

The Neuropeptide S receptor, a Gs/Gq-coupledGPCRexpressed 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.

Original languageEnglish
Pages (from-to)10132-10142
Number of pages11
JournalJournal of Neuroscience
Volume33
Issue number24
DOIs
StatePublished - 2013
Externally publishedYes

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