TY - JOUR
T1 - 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
AU - Thorsell, Annika
AU - Tapocik, Jenica D.
AU - Liu, Ke
AU - Zook, Michelle
AU - Bell, Lauren
AU - Flanigan, Meghan
AU - Patnaik, Samarjit
AU - Marugan, Juan
AU - Damadzic, Ruslan
AU - Dehdashti, Seameen J.
AU - Schwandt, Melanie L.
AU - Southall, Noel
AU - Austin, Christopher P.
AU - Eskay, Robert
AU - Ciccocioppo, Roberto
AU - Zheng, Wei
AU - Heilig, Markus
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84878831628&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.4742-12.2013
DO - 10.1523/JNEUROSCI.4742-12.2013
M3 - Article
C2 - 23761908
AN - SCOPUS:84878831628
SN - 0270-6474
VL - 33
SP - 10132
EP - 10142
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 24
ER -