# Reduced complexity mapping of oxycodone self-administration and stress responsiveness in rats

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2020 · $358,934

## Abstract

Abstract
The current opioid epidemic is fueled by the steady rise of prescription painkillers, such as OxyContin, which is
a controlled-release tablet of oxycodone. Although both clinical and animal studies have found that the rate of
onset of drug action influences the development of addiction, the exceptionally strong abuse liability of
oxycodone was manifested even when it was consumed in the controlled-release from. The heritability of
opioid addiction has been estimated to be approximately 0.5 in humans. However, few human genetics studies
have been conducted due to the difficulty in assembling the necessary large study population. In this proposal,
we aim to conduct a genetic mapping study to identify genetic factors influencing oxycodone-motivated
behaviors and vulnerability to stress, a major risk factor of opioid use disorder. To follow the clinical use
pattern, we developed an operant oral oxycodone self-administration model, where rats voluntarily consume
oral oxycodone to obtain doses that are well above clinical prescriptions. The WMI and WLI inbred strains of
rats we propose to use in this study were selectively bred from the stress-vulnerable Wistar Kyoto rat. The
WMI is an established animal model of depression and vulnerability to stress, while the WLI serves as its
isogenic control. Our preliminary data showed higher levels of oxycodone intake and oxycodone seeking in the
WMI compared to the WLI strains. We also found that females have higher oxycodone intake than males.
There were also strain and sex differences in basal plasma corticosterone (CORT) and steady-state
hippocampal glucocorticoid receptor (Nr3c1) expression. We therefore hypothesized that
genetically-determined stress response to oxycodone withdrawal drives the strain differences in oxycodone
self-administration and reinstatement of oxycodone seeking. In Aim 1, we will use a reduced complexity
mapping strategy to identify the causal genetic factors for oxycodone and stress response phenotypes. This
mapping strategy is supported by the high heritability, large effect size of strain on phenotypes, and existing
whole genome sequencing data for the WMI and WLI strains ( ~100x coverage per strain, with ~4,400 high
confidence polymorphisms between strains). In Aim 2, we will identify candidate genes using a systems
genetics approach. The low number of segregating variants between WLI and WMI greatly facilitates this goal.
In Aim 3, we will confirm causal genes using an established knockin CAG-LSL-Cas9 rat model on the WMI/WLI
genetic background.

## Key facts

- **NIH application ID:** 9971775
- **Project number:** 1R01DA048017-01A1
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Hao Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $358,934
- **Award type:** 1
- **Project period:** 2020-05-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971775

## Citation

> US National Institutes of Health, RePORTER application 9971775, Reduced complexity mapping of oxycodone self-administration and stress responsiveness in rats (1R01DA048017-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971775. Licensed CC0.

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