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

• Published in: The Journal of neuroscience 2013-06, Vol.33 (24), p.10132-10142
• Main Authors: Thorsell, Annika, Tapocik, Jenica D, Liu, Ke, Zook, Michelle, Bell, Lauren, Flanigan, Meghan, Patnaik, Samarjit, Marugan, Juan, Damadzic, Ruslan, Dehdashti, Seameen J, Schwandt, Melanie L, Southall, Noel, Austin, Christopher P, Eskay, Robert, Ciccocioppo, Roberto, Zheng, Wei, Heilig, Markus
• Format: Article
• Language: English
• Subjects: addiction; Amygdala - drug effects; Analysis of Variance; Animals; Central Nervous System Depressants - administration & dosage; Conditioning, Operant - drug effects; Cricetinae; Cricetulus; Cues; Drug Interactions; Ethanol - administration & dosage; Fluorescence Resonance Energy Transfer; Humans; Imidazoles - pharmacology; In Vitro Techniques; Locomotion - drug effects; Male; Mitogen-Activated Protein Kinases - metabolism; neuropeptide S; Organothiophosphorus Compounds - pharmacology; phosphorylation; Phosphorylation - drug effects; Protein Binding - drug effects; Radioligand Assay; Rats; Rats, Wistar; Receptors, Neuropeptide - antagonists & inhibitors; Receptors, Neuropeptide - metabolism; Reflex - drug effects; Reinforcement (Psychology); Reinforcement Schedule; Saccharin - administration & dosage; Self Administration; Sweetening Agents - administration & dosage; Transfection
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.4742-12.2013

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.