# Mesolimbic Nociceptin Signaling and Cocaine Reward Suppression

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $251,250

## Abstract

Addiction is a pressing public health concern that impacts millions of people in the U.S, causing
a sizable burden on the health care system and thousands of unnecessary deaths, 1 in 5 of which
are due to psychostimulant abuse, such as cocaine. However, the mechanisms that control
response to cocaine are not clearly defined, and there is a pressing need to understand these
mechanisms. The current study will explore the possibility that the neuropeptide, NOF/Q (aka:
nociceptin), is a potent cocaine reward suppressor that acts in mesolimbic terminal regions of the
nucleus accumbens (NAc). Preliminary data strongly support that NOF/Q signaling in NAc blocks
cocaine reward, and that NOF/Q can act directly upon DAergic terminals within NAc. However,
the mechanisms and circuitry that mediate NOF/Q reward suppression in NAc are completely
undefined, nor is it known whether there is basal NOF/Q tone in NAc that constitutively sets
sensitivity to rewarding substances. The proposed exploratory studies will leverage a variety of
cutting-edge viral and genetic tools to fully characterize NOF/Q tone and effects on reward in
NAc, as well as the NOF/Q circuitry innervating NAc and that likely serve as an endogenous
reward suppression system. Studies in Aim 1 will provide an in-depth analysis of cocaine reward
suppression by NOF/Q in male and female mice, and leverage optogenetics in PNOCCre mice to
determine whether endogenous NOF/Q signaling is sufficient to suppress cocaine reward.
Studies in Aim 2 will leverage NOPRfl/fl mice to test whether NOF/Q signaling on DAergic
mesolimbic terminals is required for cocaine suppression by NOF/Q. In addition, Aim 2 studies
will use PNOCCre mice to retrogradely trace NOF/Q afferents in NAc, to the likely source of
endogenous NOF/Q. Taken together, these studies will provide a fundamental understanding of
the potential for NOF/Q signaling as powerful suppressant of cocaine reward, and will shed light
on an intrinsic mechanism that sets reward tone. Importantly, the findings will lay the necessary
groundwork for future work aimed at understanding the mechanisms and specific circuits that
mediate NOF/Q reward suppression.

## Key facts

- **NIH application ID:** 10984872
- **Project number:** 1R21DA058804-01A1
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Haley E Melikian
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $251,250
- **Award type:** 1
- **Project period:** 2024-06-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984872

## Citation

> US National Institutes of Health, RePORTER application 10984872, Mesolimbic Nociceptin Signaling and Cocaine Reward Suppression (1R21DA058804-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10984872. Licensed CC0.

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