# Identifying genomic loci related to vulnerability to opioid addiction

> **NIH NIH U01** · UNIVERSITY OF MINNESOTA · 2020 · $637,590

## Abstract

Between 8-12% of people exposed to opioids develop opioid use disorder (OUD). Developing more effective
preventions and treatments for OUD requires a better understanding of genomic and epigenetic mechanisms
that underlie individual vulnerability to distinct stages along the OUD trajectory (e.g., initial use, compulsive
use, relapse). The overall goal of this proposal is to use an outbred rat model (Sprague-Dawley) to identify
novel downstream genes and upstream regulators of gene transcription involved in 3 behavioral phenotypes
associated with distinct stages along the OUD trajectory. By comparing rats that show high versus low levels of
addiction-like behavior at each stage, we will be able to identify changes in gene expression and their
regulation associated specifically with susceptibility to opioid addiction from among the numerous effects of
opioids that are unrelated to addiction. Anhedonia produced during withdrawal from acute morphine (i.e.,
withdrawal-induced anhedonia, WIA) will be used as an addiction phenotype of the earliest phase of OUD, i.e.
prior to voluntary drug consumption. We have previously found that WIA is more strongly associated with a
range of measures of subsequent i.v. morphine self-administration (SA) than these SA measures are with one
another. Economic demand for morphine and reinstatement after extinction will serve as measures of drug
reinforcement efficacy and propensity for relapse, respectively, after extensive morphine SA. To identify
vulnerability-related genomic targets, we will use Next-Generation Sequencing (NGS) techniques and
advanced bioinformatic tools to compare transcriptomic and epigenomic differences in rats exhibiting high
versus low levels of WIA (Aim 1), demand (Aim 2) or reinstatement (Aim 3). Our epigenomic assays will map
loci of chromosomal accessibility (using ATAC-seq) and of the stable chromatin mark H3K4me3 (using ChIP-
seq). We will overlay each of these data sets onto RNA-seq data to identify genes showing differential
activation in High- versus Low-Susceptibility rats, as well as upstream regulators of these transcriptional
effects. These assays will focus on the medial prefrontal cortex (mPFC), a node within the mesocorticolimbic
system that plays a pivotal role in addiction. We will also overlay epigenomic maps derived from our studies
onto genotyping data derived from larger studies of Heterogeneous Stock (HS) rats manifesting High- versus
Low addiction-related behavioral phenotypes (e.g., drug intake, impulsivity), in other NIDA Animal Genetics
Consortium U01/P50 projects. We hypothesize that these comparisons will yield a set of downstream genes
and upstream regulators associated with individual differences in early vulnerability to addiction-like behavior
and its severity once established. We further hypothesize that our transcriptomic and epigenomic data will
provide a viable roadmap for identifying genetic variants from larger genomic datasets associated with
individual dif...

## Key facts

- **NIH application ID:** 10057780
- **Project number:** 1U01DA051993-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** JONATHAN GEWIRTZ
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $637,590
- **Award type:** 1
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10057780

## Citation

> US National Institutes of Health, RePORTER application 10057780, Identifying genomic loci related to vulnerability to opioid addiction (1U01DA051993-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10057780. Licensed CC0.

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