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

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).