Antagonism of the neuropeptide S receptor with RTI-118 decreases cocaine self-administration and cocaine-seeking behavior in rats

Abstract

Neuropeptide S (NPS) is a neuromodulatory peptide, acting via a G-protein-coupled receptor to regulate sleep, anxiety and behavioral arousal. Recent research has found that intracerebroventricular NPS can increase cocaine and alcohol self-administration in rodents, suggesting a key role in reward-related neurocircuitry. It is hypothesized that antagonism of the NPS system might represent a novel strategy for the pharmacological treatment of cocaine abuse. To this end, a small-molecule NPSR antagonist (RTI-118) was developed and tested in animal models of cocaine seeking and cocaine taking. Male Wistar rats (n=54) trained to self-administer cocaine and food under a concurrent alternating FR4 schedule exhibited specific dose-dependent decreases in cocaine intake when administered RTI-118. RTI-118 also decreased the reinstatement of extinguished cocaine-seeking behavior induced by conditioned cues, yohimbine and a priming dose of cocaine. These data support the hypothesis that antagonism of the neuropeptide S receptor may ultimately show efficacy in reducing cocaine use and relapse.

Effects of the neuropeptide S receptor antagonist RTI-118 on abuse-related facilitation of intracranial self-stimulation produced by cocaine and methylenedioxypyrovalerone (MDPV) in rats

“…The order of testing was varied across subjects using a Latin-square design. Doses and pretreatment times for cocaine, MDPV, RTI-118 and U69,593 were based on previous studies (Bonano et al, 2013; Rosenberg et al, 2013; Schmoutz et al, 2012; Tomasiewicz et al, 2008). Test sessions were completed on Tuesdays and Fridays, and three-component training sessions were conducted on all other weekdays.…”

“…RTI-118 (1–20 mg/kg i.p.) also blocked cocaine, cue-, and stress-induced reinstatement of extinguished cocaine self-administration (Schmoutz et al, 2012). The potency of RTI-118 to reduce abuse-related cocaine effects in rats was similar to its potency to block locomotor activation elicited by intracerebroventricular NPS in mice (Hassler et al, 2014).…”

“…NPS receptors are distributed in multiple brain regions, including ventral tegmental area, amygdala, hippocampus and hypothalamus (Leonard and Ring, 2011; Xu et al, 2007). NPS receptor agonists produce an unusual behavioral profile that includes increased wakefulness, locomotor stimulation and anxiolytic-like effects (Dal Ben et al, 2011), and both NPS and its receptor have been implicated in effects produced by abused drugs like cocaine (Guerrini et al, 2010; Kallupi et al, 2010; Paneda et al, 2009; Schmoutz et al, 2012). One outcome of these studies has been the hypothesis that NPS receptor antagonists may have utility as candidate medications for treatment of addiction to cocaine and other abused drugs (Guerrini et al, 2010).…”

“…RTI-118 (3-oxo-1,1-diphenyl-N-(2-(piperidin-1-yl)ethyl)tetrahydro-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxamide) is a novel NPS receptor antagonist that has been tested in studies of cocaine self-administration and reinstatement of extinguished cocaine self-administration in rats (Schmoutz et al, 2012; Zhang et al, 2008). Specifically, RTI-118 (5–30 mg/kg i.p.)…”

“…Specifically, RTI-118 (5–30 mg/kg i.p.) produced a dose-dependent and nearly complete elimination of cocaine self-administration, and was more potent and efficacious to reduce cocaine self-administration than food-maintained responding (Schmoutz et al, 2012). RTI-118 (1–20 mg/kg i.p.)…”