# Behavior-based discovery of small-molecule modulators of neurochemical signaling pathways that underlie addiction

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $646,068

## Abstract

PROJECT SUMMARY
Addiction is a complex pathology of neural circuits that function in reward-processing, impulse control, and
goal-directed behaviors. Small molecules targeting neuromodulator signaling pathways that function in these
circuits are important therapeutics for the treatment of addiction. There is an urgent need to improve the
pharmacology used to treat addiction. To address this need, we have developed methods that uses behavior-
based screens to interrogate a novel source of natural products for effects on neuromodulator signaling in the
nervous system of a microscopic animal - the nematode C. elegans. The natural products that we will screen
are microbial metabolites that have eluded detection because they are not expressed under basal conditions
but can only be elicited by environmental triggers. This microbial 'dark metabolome' contains small molecules
with a wide variety of biological activities. These compounds have not yet been assayed for effects on the
animal nervous system, and they constitute a rich and untapped resource for novel psychopharmacology.
Through screens designed to demonstrate proof-of-concept, we have already identified compounds that
strongly and specifically act on a circuit that uses neuropeptides and serotonin to generate behavior. We have
also designed behavior-based screens for novel modulators of dopamine signaling. In addition to providing the
opportunity to perform high-throughput behavior-based screens, the powerful genetics of the C. elegans model
allows assignment of neuroactive compounds to specific neuromodulator signaling pathways. Successful
completion of the aims of this project will generate enhanced and expanded libraries of novel natural products
never before assayed for effects on the nervous system, identify novel small-molecule regulators of neural
circuits, and match those compounds to specific neuromodulator signaling systems integral to the pathology of
addiction.

## Key facts

- **NIH application ID:** 10489563
- **Project number:** 1R01DA056358-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Christopher Fang-Yen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $646,068
- **Award type:** 1
- **Project period:** 2022-07-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489563

## Citation

> US National Institutes of Health, RePORTER application 10489563, Behavior-based discovery of small-molecule modulators of neurochemical signaling pathways that underlie addiction (1R01DA056358-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10489563. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*