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

Neuropeptide S (NPS) is a neuromodulatory peptide that acts via a G protein-coupled receptor. Centrally administered NPS suppresses anxiety-like behaviors in rodents while producing a paradoxical increase in arousal. In addition, NPS increases drug-seeking behavior when administered during cue-induced reinstatement. Conversely, an NPS receptor (NPSR) antagonist, RTI-118, decreases cocaine-seeking behavior. A biased NPSR ligand, RTI-263, produces anxiolytic-like effects and has memory-enhancing effects similar to those of NPS but without the increase in arousal. In the present study, we show that RTI-263 decreased cocaine seeking by both male and female rats during cue-induced reinstatement. However, RTI-263 did not modulate the animals' behaviors during natural reward paradigms, such as palatable food intake, feeding during a fasting state, and cue-induced reinstatement of sucrose seeking. Therefore, NPSR biased agonists are a potential pharmacotherapy for substance use disorder because of the combined benefits of decreased drug seeking and the suppression of anxiety.