# Leveraging Functional Selectivity in the Neurotensin Receptor 1-Mediated Treatment of Addiction

> **NIH NIH K99** · DUKE UNIVERSITY · 2020 · $119,463

## Abstract

Abstract: Opioid and psychostimulant addictions are large and growing public health concerns that are
inadequately managed with available therapeutics. The objective of this proposal directly addresses this unmet
clinical need, as it includes the evaluation of a novel anti-addiction therapeutic strategy. A shared feature of
addictive drugs is their ability to induce inappropriate activation of the mesolimbic dopamine system. Restoration
of dopamine signaling homeostasis may be achieved by targeting the G protein-coupled receptor (GPCR)
neurotensin receptor 1 (NTR1). NTR1 modulates dopamine signaling via action at putative NTR1/dopamine
receptor D2 (D2R) complexes. The efficacy of peptide or small molecule NTR1 agonists in animal models of
addiction have made them highly desirable but they all have side effects. NTR1, like other GPCRs, signals
through both G protein- and β-arrestin-mediated pathways. Recently, we have developed and characterized a
novel class of small molecule NTR1 ligands, typified by compound SBI-553, which activates β-arrestin without
stimulating G protein signaling. This type of functional selectivity/biased siganling presents an opportunity to
produce more directed physiological action and reduce unwanted side effects. My promising initial findings
suggest that SBI-553 attenuates opioid and stimulant-associated behaviors in mice without the hypotension and
hypothermia characteristic of unbiased NTR1 agonism. The objectives of this application are to elucidate the
mechanism by which β-arrestin biased NTR1 ligands attenuate drug-associated behaviors and validate their
therapeutic potential by integrating murine self-administration and functional neuroimaging. My central
hypothesis is that selective β-arrestin activation at NTR1 attenuates addiction-like behaviors and associated
changes in regional brain metabolism through antagonism of D2R function. This hypothesis will be tested by
pursuing three specific aims, using SBI-553 as a tool compound. I will first (1) K99) define the behavioral effects
of β-arrestin biased NTR1 ligands by conducting self-administration studies in genetically engineered mice. I will
then (2) K99) determine the physiological effects of β-arrestin biased NTR1 ligands using state-of-the-art small
animal positron emission tomography/computed tomography (PET/CT). Finally, I will use my new training in
murine self-administration and PET/CT to independently (3) R00) evaluate the contribution of D2R to the effects
of β-arrestin biased NTR1 ligands. Pursuit of these aims requires interdisciplinary training in animal models
of addiction and neuroimaging to complement my previous studies in molecular biology. Therefore, I have
assembled expert collaborators into an interdisciplinary mentoring committee, chaired by Drs. Marc Caron
(Mentor) and Lawrence Barak (Co-Mentor). The Caron laboratory at Duke University is uniquely well-positioned
to answer questions regarding biased GPCR signaling. We have developed an in...

## Key facts

- **NIH application ID:** 9948614
- **Project number:** 5K99DA048970-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Lauren M Slosky
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $119,463
- **Award type:** 5
- **Project period:** 2019-06-15 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948614

## Citation

> US National Institutes of Health, RePORTER application 9948614, Leveraging Functional Selectivity in the Neurotensin Receptor 1-Mediated Treatment of Addiction (5K99DA048970-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9948614. Licensed CC0.

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