# Glucocorticoid Receptor Dysregulation: a Genetic Risk Factor for Excessive Alcohol Consumption in High Drinking in the Dark (HDID-1) Mice

> **NIH NIH F32** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $65,310

## Abstract

Project Summary
Binge drinking has significant negative consequences for health and society, and is a major predictor for the
development of an alcohol use disorder (AUD). The High Drinking in the Dark (HDID-1) line of mice, selectively
bred for high blood ethanol concentrations (BECs) in a limited access binge-like drinking task, exhibit
differential gene expression of a number of glucocorticoid receptor (GR) regulator proteins relative to their low-
drinking founder line, HS/Npt. GR expression has been shown to be altered in response to chronic alcohol
exposure and to promote further alcohol intake in dependence-like models, but GR dysregulation has not yet
been identified as a genetic risk factor for excessive alcohol consumption in non-dependent animals.
Preliminary data show that HDID-1 mice exhibit a dose-dependent reduction in binge drinking when given
mifepristone, a GR antagonist, after only being exposed to a single 2-hour ethanol drinking session. These
data suggest that selection for high BECs in the HDID-1 line has led to a sensitized GR system that may
promote binge drinking. The goal of this fellowship project is to investigate the role of enhanced GR activity as
a genetic risk factor for excessive alcohol consumption. Aim 1 will characterize GR expression and
transcriptional activity in the brains of the high-drinking HDID-1 mice relative to the low-drinking founder line,
HS/Npt. Specifically, GR and GR-related signaling genes in the nucleus accumbens (NAc) will be quantified,
as GR expression in the NAc has previously been shown to promote alcohol intake. Aim 2 will determine
whether pharmacological manipulation of GR in the NAc can bi-directionally modulate binge drinking. Bilateral
cannulation will be performed in the NAc of (1) HDID-1 mice to deliver a GR antagonist and attempt to reduce
binge drinking, and of (2) HS/Npt mice to deliver a GR agonist and attempt to increase binge drinking. The
results of this aim will determine whether GR manipulation in the NAc is sufficient to alter binge drinking. Aim 3
will investigate whether GR antagonism in HDID-1 mice is sufficient to prevent escalated drinking after chronic
intermittent ethanol (CIE) vapor exposure, a model of relapse-like drinking. The results of this aim will
determine whether the same mechanisms driving binge drinking in HDID-1 mice also underlie relapse-like
drinking. Aim 1 utilizes a basic science approach to examine molecular pathways that may have been altered
through selection pressure, while Aims 2 and 3 will provide translational insight into potential pharmacological
treatments for patients with AUD. Together, the experiments in this project will provide a better understanding
of how GR activity in the brain contributes to excessive alcohol consumption in both non-dependent and
dependent-like models of drinking.

## Key facts

- **NIH application ID:** 9948477
- **Project number:** 5F32AA027692-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Antonia Savarese
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 5
- **Project period:** 2019-05-16 → 2021-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948477

## Citation

> US National Institutes of Health, RePORTER application 9948477, Glucocorticoid Receptor Dysregulation: a Genetic Risk Factor for Excessive Alcohol Consumption in High Drinking in the Dark (HDID-1) Mice (5F32AA027692-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9948477. Licensed CC0.

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