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

Abstract

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.

Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects

“…In contrast, acute administration of a lower dose of EtOH (1g/kg) significantly increased pERK in various regions including the NAc, and CeA in the D1-R and neuropeptide S receptor dependent manner 236,237 . The acute EtOH-induced c-fos induction in the medial Amy was inhibited by the MEK inhibitor, U0126 238 .…”

Operant ethanol self-administration increases extracellular-signal regulated protein kinase (ERK) phosphorylation in reward-related brain regions: selective regulation of positive reinforcement in the prefrontal cortex of C57BL/6J mice

“…The ERK/MAPK pathway in the central nucleus of the amygdala (CeA) is activated in response to acute ethanol injection and home cage 24-h and binge 4-h self-administration, (Ibba et al 2009; Spanos et al 2012; Thorsell et al 2013). Likewise, we found that 30 days of operant ethanol self-administration significantly increased pERK1/2 IHC in the CeA but not BLA (Figure 1C).…”

Structure–Activity Relationship of Imidazopyridinium Analogues as Antagonists of Neuropeptide S Receptor

“…While we are aware that the total drug concentration in the brain may not be a good indicator of a pharmacodynamic effect, 33 detailed in vivo studies in rat alcohol models with 20e show efficacy with an IP dose of 1.0 mpk. 34 …”

“…Recently, we completed the evaluation of 20e in animal models of alcoholism where antagonism of NPSR is predicted to have an effect. 34 Results of these studies show a supression of alcohol self administartion in rats with a dose as low as 1 mpk. We also show that, at the same dose, 20e is able to reduce alcohol induced ERK phosphorylation in the central amygdala of these rats.…”