# 8/8: INIA Stress and Chronic Alcohol Interactions: Glucocorticoid antagonists in heavy drinkers:effects on fMRI connectivity, withdrawal and drinking

> **NIH NIH U01** · JOHNS HOPKINS UNIVERSITY · 2020 · $412,236

## Abstract

Cortisol (CORT) is a glucocorticoid hormone, often associated with response to stress and playing a key role in
alcohol use and problems. First, acute alcohol administration increases CORT, which in turn amplifies the
mesolimbic dopamine reward signal. Second, alcohol withdrawal elevates CORT levels in AUD compared with
healthy control subjects, and CORT levels in early abstinence predict subsequent relapse to drinking. Finally,
the magnitude of CORT response to external stressors predicts motivation to work for and consumption of
alcohol in the human laboratory and in the natural environment. Importantly, recent studies in rodents and
humans have demonstrated that blocking CORT activity using a glucocorticoid receptor (GR) antagonist
reduces these effects of CORT on alcohol behaviors, indicating a causal role for glucocorticoids in these
relationships. The proposed research will test the effectiveness of two glucocorticoid receptor antagonists with
different receptor binding and side-effect profiles. In alcohol use disorder (AUD) and matched healthy control
(HC) men and women, the proposed research examines MIFE, with demonstrated preclinical effects on
drinking-related behaviors, and CORT125134, a newer medication with improved safety profile but as yet
unexamined efficacy for AUD, on a breadth of alcohol-related measures. All subjects will be randomized to
daily MIFE, CORT125134 or placebo. Before and during medication, AUD and HC subjects undergo fMRI
scanning measuring resting-state functional connectivity and alcohol cue-induced brain activation focused on
brain reward and stress pathways. All subjects are admitted to the Clinical Research Unit; AUD subjects
undergo supervised alcohol withdrawal with daily measurements of alcohol craving and symptom severity.
Using validated human laboratory procedures in AUD subjects, we examine the effects of stress on motivation
to drink and alcohol sensitivity/reward as a function of GR antagonism. This work will help pave the way for
improved pharmacotherapies that target stress and reward pathways in the brain involved in initiating and
maintaining drinking.

## Key facts

- **NIH application ID:** 9879666
- **Project number:** 5U01AA020890-09
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** MARY E MCCAUL
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,236
- **Award type:** 5
- **Project period:** 2012-02-15 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879666

## Citation

> US National Institutes of Health, RePORTER application 9879666, 8/8: INIA Stress and Chronic Alcohol Interactions: Glucocorticoid antagonists in heavy drinkers:effects on fMRI connectivity, withdrawal and drinking (5U01AA020890-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9879666. Licensed CC0.

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