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

  • Neuropharmacology. 2023 Dec 15:241:109743. doi: 10.1016/j.neuropharm.2023.109743.
Yuanli Huang  1 ,  Alaina Wojciechowski  1 ,  Kyle Feldman  1 ,  Robert Ettaro  1 ,  Kaliana Veros  1 ,  Morgan Ritter  1 ,  Paula Carvalho Costa  1 ,  Jacob DiStasio  1 ,  Jennifer J Peirick  2 ,  Kathryn J Reissner  3 ,  Scott P Runyon  4 ,  Stewart D Clark  5
Affiliations
  • 1. Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY 14214, USA.
  • 2. Laboratory Animal Facilities, University at Buffalo, Buffalo, NY 14214, USA.
  • 3. Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 4. Research Triangle Institute, Center for Drug Discovery, Research Triangle Park, NC 27709, USA.
  • 5. Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY 14214, USA. Electronic address: [email protected].
PMID: 37820934 DOI: 10.1016/j.neuropharm.2023.109743
Abstract

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.

Keywords
Anxiolytic; Cocaine seeking; Neuropeptide S.
Products