# Modulating Endogenous Opiate Signaling to Reverse Stress-Induced Deficits in Reward Processing

> **NIH NIH R21** · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · 2024 · $459,613

## Abstract

Project Abstract
Millions of Americans suffer from deficits in reward processing, in the context of psychiatric disorders including
major depressive disorder and schizophrenia. Disrupted reward processing leads to worse outcomes, yet
current treatments poorly treat this symptom and new treatments are urgently needed. Recent evidence that
mu opioid antagonists function as antidepressants suggest the opioid system as a promising line for
developing novel treatments. We hypothesize that increasing endogenous enkephalins by using molecules
(DENKIs) that inhibit the degradation of this endogenous class of opioid peptides will reverse reward seeking
deficits without raising the liability for substance use disorders. To test this hypothesis and extend our
preliminary data, we will administer a DENKI to chronically stressed mice and record in vivo neural activity in
the reward circuitry (ventral tegmental area (VTA) and nucleus accumbens (NAc)) as the freely moving mice
engage in a reward task that assesses different aspects of reward processing. Using KO mice and receptor-
specific antagonists, in Aim 1, we will determine if these effects are mediated by MOR and in Aim 2, test
whether they are mediated by delta opioid receptor (DOR). We will also confirm that DENKI administration is
not inherently rewarding. Successful completion of these aims will yield novel insights into how the opioid
system influence reward circuity activity during behavior and establish the basis for more detailed study of
endogenous enkephalin modulators as treatments for the anhedonia commonly seen in psychiatric disorders.

## Key facts

- **NIH application ID:** 10987909
- **Project number:** 1R21MH136484-01A1
- **Recipient organization:** NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
- **Principal Investigator:** Alexander Harris
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $459,613
- **Award type:** 1
- **Project period:** 2024-09-02 → 2026-09-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10987909

## Citation

> US National Institutes of Health, RePORTER application 10987909, Modulating Endogenous Opiate Signaling to Reverse Stress-Induced Deficits in Reward Processing (1R21MH136484-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10987909. Licensed CC0.

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