# PROJECT 1: Targeting stress-reactivity and noradrenergic mechanisms for sex-appropriate alcohol use disorder treatment.

> **NIH NIH U54** · YALE UNIVERSITY · 2020 · $344,261

## Abstract

Rates of alcohol use disorders (AUDs) have increased by 84% in women over the past 10 years. Several
lines of evidence indicate that drinking behavior in women is more likely to be motivated by affect regulation
and stress, whereas drinking in men is motivated by stimulation and alcohol-related positive reinforcement. To
date, there has been no concerted effort to develop medications for AUD that target factors which differentially
maintain drinking in women. Using Koob & Volkow’s heuristic framework of the addiction cycle162, we will target
the ‘dark side of addiction’ for sex-appropriate AUD medication development. Project 1 will focus on a single
noradrenergic target, guanfacine, in order to be fully powered to examine sex by medication effects on
treatment outcomes. Importantly, Project 1 will provide a template to mechanistically evaluate sex differences
in AUD medication development. Our preliminary results demonstrate that guanfacine robustly reduces the
quantity, frequency, and percentage of binge episodes of alcohol consumption in both women and men, with
possibly larger effects in women. The neural mechanisms underlying this effect appear to be sex-dependent.
For women, guanfacine reduces drinking by reducing stress reactivity. For men, the evidence is less clear, but
guanfacine appears to target alcohol-related positive reinforcement. Consistent with the aim of the Yale-
SCORE to develop sex-appropriate therapeutics for AUD, and with the input and feedback of Project 2 & 3
Leads, we plan to conduct the first, fully-powered, mechanistic Phase 2b, double-blind, placebo-controlled,
parallel-group study to examine sex differences in guanfacine's effect on: 1) counteracting stress- and
stimulation-based drinking behavior in the laboratory and 2) improving clinical outcomes during a subsequent
treatment phase. Importantly, we will examine the safety of guanfacine and potential sex differences in
mechanisms underlying drinking (e.g., craving, mood, cognitive function, cardiovascular reactivity, markers of
HPA-axis activity, cytokines, markers of alcohol-metabolism, sex steroid hormones, and subjective alcohol
effects). Additionally, we will use an innovative biosensor system to assess naturalistic drinking during the 6-
week treatment period. To our knowledge, this will be the first clinical trial investigation to prospectively
examine sex differences in the therapeutic potential and associated mechanisms of a selective α2a agonist,
guanfacine, for the treatment of AUD. Synthesis of findings across the three projects will identify new
neurobiological targets for sex-appropriate therapeutics for AUD.

## Key facts

- **NIH application ID:** 9854091
- **Project number:** 1U54AA027989-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Sherry Ann McKee
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $344,261
- **Award type:** 1
- **Project period:** 2020-03-10 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854091

## Citation

> US National Institutes of Health, RePORTER application 9854091, PROJECT 1: Targeting stress-reactivity and noradrenergic mechanisms for sex-appropriate alcohol use disorder treatment. (1U54AA027989-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9854091. Licensed CC0.

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