# Understanding endogenous opioid drive of alcohol consumption

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $361,285

## Abstract

PROJECT SUMMARY
Endogenous opioids released in the Central Nervous System by drinking alcohol promote continued
consumption. The endogenous opioid peptides are fragments of larger precursor peptides (preproenkephalin
(PPENK), preprodynorphin (PPDYN) and pro-opiomelanocortin (POMC)) are implicated in regulating alcohol
intake. The fragments that are actually released are unknown, however the known POMC and PPENK derived
peptide fragments act both the mu and delta opioid receptors (MORs and DORs, respectively). We found that
endogenous opioids acting at the DOR can protect against high levels of alcohol consumption, while opioids
acting the MOR promote alcohol consumption. To better understand how endogenous opioids control ethanol
consumption and to develop new opioid based therapeutic agents we need to determine how MORs and
DORs are dynamically regulated and interact. Furthermore, a full understanding of how they regulate ethanol
consumption will require identification of which opioid peptides fragments are released by drinking and then
testing the action of these peptides at synaptic elements that express both receptors and are involved in
regulating ethanol consumption. The ventral tegmental area (VTA) is a site where opioids act to control
ethanol consumption. MOR selective antagonists injected into the VTA reduce while DOR antagonists increase
ethanol consumption. Both MOR and DOR selective ligands have synaptic actions in the VTA that correlate
with alcohol consumption. In this project we will study the interaction of MOR, DOR and kappa opioid receptor
agonists on VTA synaptic function. We will collect and identify endogenous opioid peptides released in the
VTA during voluntary ethanol drinking, then test the action of these peptides on opioid receptor expressing
synaptic elements in the VTA. We will also use optogenetic approaches to activate and inhibit specific sources
of opioid peptide input to the VTA to determine the critical circuit inputs that modify drinking behavior. This
information will be used to better understand the molecular mechanisms that promote and inhibit alcohol
consumption and to design new, more effective opioid ligands for the treatment of alcohol abuse.

## Key facts

- **NIH application ID:** 9966833
- **Project number:** 5R01AA026609-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Elyssa Margolis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $361,285
- **Award type:** 5
- **Project period:** 2018-09-10 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966833

## Citation

> US National Institutes of Health, RePORTER application 9966833, Understanding endogenous opioid drive of alcohol consumption (5R01AA026609-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9966833. Licensed CC0.

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