# Validation of ghrelin hydrolysis as an effective approach to treatment of substance use disorders

> **NIH NIH U18** · UNIVERSITY OF KENTUCKY · 2020 · $229,500

## Abstract

About 10 percent of American adults have struggled with substance use disorders (SUDs). In some SUDs,
such as cocaine and methamphetamine (METH) use disorders, there are no approved medications. For other
substances, such as alcohol, nicotine, and opioids, there are approved medications available, but relapse rates
are high. It is highly desirable to develop improved treatments for SUDs. Recently reported studies have revealed
an interesting role of ghrelin in drug abuse and award-relevant behaviors. Ghrelin, known as a 28 amino-acid
peptide (GSSFLSPEHQKAQQRKESKKPPAKLQPR) acylated at Ser3 by a fatty acid, is produced in the stomach
and travels to the brain through blood circulation. In the brain, ghrelin acts on ghrelin (or growth hormone
secretagogue) receptor (GHSR) to stimulate the mesolimbic dopamine reward pathway and increase rewarding
behaviors in rodents. Ghrelin receptor antagonism has been shown to attenuate METH-, amphetamine-,
cocaine-, nicotine-, fentanyl-, morphine-, and alcohol-induced rewarding effects. For example, administration of
a selective GHSR antagonist significantly and dose-dependently attenuated morphine-induced conditioned
placed preference (CPP) and dopamine sensitization, and attenuated METH self-administration, tendency to
relapse, and METH-induced CPP. In addition, pretreatment with a selective GHSR antagonist significantly and
dose‐dependently reduced the manifestation of fentanyl‐CPP and reduced the fentanyl‐seeking/relapse‐like
behavior in rats. In fact, GHSR antagonism is one of the NIDA’s 10 Most-Wanted targets for opioid user disorder
medication development. On the other hand, GHSR possesses a naturally high constitutive activity (in the
absence of ghrelin ligand) representing 50% of its maximal activity. Due to the ghrelin receptor’s diverse
regulatory roles associated with its constitutive activity, GHSR antagonism could also result in unwanted adverse
effects. Thus, alternative strategies targeting ghrelin itself could be a more interesting approach. However,
whether targeting ghrelin itself would be effective to attenuate the drug rewarding effects remains controversial
in literature as ghrelin levels before and after treatment were not measured in previous animal studies using
ghrelin sequestering approaches. It is unknown whether any of the previously used approaches was able to
decrease the ghrelin level significantly enough to attenuate the substance reward. We propose to develop and
test an efficient ghrelin hydrolase which can be used as a safe and effective ghrelin modulator to attenuate
substance rewarding effects as effective as a GHSR antagonist but without interacting with any brain
receptors/transporters and to treat SUDs, including METH and opioid use disorders etc. Accomplishment of this
investigation will determine whether ghrelin itself is a truly effective target and whether the specific ghrelin
hydrolase as a ghrelin modulator is truly effective for treatment of SUDs. If the answers are ...

## Key facts

- **NIH application ID:** 10102306
- **Project number:** 1U18DA052319-01
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Fang Zheng
- **Activity code:** U18 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $229,500
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102306

## Citation

> US National Institutes of Health, RePORTER application 10102306, Validation of ghrelin hydrolysis as an effective approach to treatment of substance use disorders (1U18DA052319-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10102306. Licensed CC0.

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