# Dissecting the Paradox of the Neuropeptide S System

> **NIH NIH R21** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2020 · $199,375

## Abstract

Project Summary
Substance abuse disorders have a devastating impact on individuals, families, and society. Present
pharmacological treatments do not fully ameliorate patients' symptoms and in many cases are unable to treat
the full spectrum of symptoms. Therefore, it is paramount to identify new targets for pharmacological
intervention. To do this we must better understand the neural mechanisms underpinning drug-taking behavior
and drug-mediated reward.
The Neuropeptide S (NPS) system when activated in mice enhances memory formation and produces both
anxiolytic-like and hyperlocomotor effects. This is a unique behavioral profile, and if pharmacologically targeted
could have multiple therapeutic benefits. Based on research conducted in our lab, we have identified the first
and only biased NPSR agonist (RTI-263). It retains full agonist properties in calcium mobilization assays, but
has attenuated ability to increase cAMP levels. Importantly, in mice, RTI-263 evokes similar anxiolytic-like and
memory enhancing effects as NPS. However, RTI-263 is unable to produce the pronounced increase in
locomotor activity and actually blocks hyperlocomotion induced by exogenously administered NPS. Other
compounds that block this hyperlocomotion, NPSR antagonists, are known to reduce cocaine seeking in
rodents. Therefore, we hypothesize that RTI-263 will display dual properties whereby it will likely
simultaneously produce anxiolysis and curb cocaine intake. This has obvious benefit as relapse into the cycle
of drug taking in humans is often associated with stress and anxiety producing life events.
The goals of this project are to better elucidate the circuitry of the NPS-system by determining the role of
particular subpopulations of NPSR-expressing neurons in core behaviors it is known to modulate. In addition,
we will show proof-of-concept that NPSR ligands with similar pharmacological profiles as RTI-263 have
potential as therapeutics for cocaine abuse. NPSR is a potential target for the development of therapeutics for
addiction and other neuropsychiatric disorders related to the dysregulation of stress and anxiety.

## Key facts

- **NIH application ID:** 9869881
- **Project number:** 5R21DA045825-02
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Stewart Donaldson Clark
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $199,375
- **Award type:** 5
- **Project period:** 2019-02-15 → 2022-02-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869881

## Citation

> US National Institutes of Health, RePORTER application 9869881, Dissecting the Paradox of the Neuropeptide S System (5R21DA045825-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9869881. Licensed CC0.

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