RTI‐263, a biased NPS receptor agonist that retains anxiolytic effect, attenuates cocaine‐seeking behavior in rats

Abstract

Neuropeptide S (NPS) is a modulatory peptide, activating a G protein‐coupled receptor (NPSR) that has been shown to have memory‐enhancing, anxiolytic‐like, and hyper‐locomotive, and drug reinforcement effects in rodents. The NPS system has emerged as a candidate therapeutic target as NPSR antagonists were shown to attenuate reinstatement responding of drug seeking behavior (cocaine). A recently disclosed NPSR biased agonist, RTI‐263, blocks NPS induced hyperlocomotor but produces anxiolytic‐like and learning effects similar to NPS in vivo. Therefore, as triggers of drug taking behavior are often related to stressful life circumstances, RTI‐263 may be an ideal pharmacotherapeutic for substance use disorders due to its anxiolytic effects. Our current research demonstrates that the NPSR biased agonist RTI‐263 (1 and 10nmole, intracerebroventricular) attenuates cue‐induced cocaine reinstatement under a concurrent alternating FR4 schedule in self‐administration experiment. Future research will focus on whether the effect of RTI‐263 is specific to drug reward or is more generalizable (e.g. food reward). This research is supported by NIH grant R21DA045825 (Dr. Stewart Clark).