# Gsk3b in ethanol consumption and as a therapeutic target for alcohol use disorder

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $314,381

## Abstract

This project studies the role of glycogen synthase kinase-3 beta (GSK3B) in modulation of
ethanol consumption. GSK3B has been implicated as having an important role in synaptic
plasticity and learning. Additionally, GSK3B has been suggested to modulate behaviors for
other drugs of abuse. GSK3B has been shown by multiple studies to be inhibited by
phosphorylation on residue Ser9 in the medial prefrontal cortex (mPFC) and nucleus
accumbens (NAc) of rodents after acute ethanol exposure. However, we recently found that
prolonged ethanol consumption causes habituation of this inhibition of GSK3B by acute ethanol
in PFC. Our recent studies on rodent drinking behavior show that pharmacological or genetic
targeting inhibition of GSK3B in forebrain Camk2a+ neurons will decrease ethanol consumption.
However, the mechanisms of GSK3B modulation of ethanol consumption are unknown. This
proposal will perform a detailed analysis of ethanol regulation of GSK3B activity, and the
specific cellular and neural circuits involved in GSK3B modulation of ethanol consumption. Aim
1 will investigate cellular sites of acute ethanol-induced GSK3B phosphorylation (inhibition) in
mPFC and study the time course, duration and mechanisms of chronic ethanol-induced
habituation of the acute response to ethanol. Viral vector and Cre-LoxP genetic targeting will be
used in Aim 2 to identify whether Camk2a-positive neurons in mPFC are the critical site for
GSK3B modulation of ethanol behaviors, and will identify downstream circuits of these neurons.
RNAseq studies and bioinformatics in Aim 3 will then study genomic responses downstream of
GSK3B following selective deletion or over-expression, thus identifying critical gene networks
functioning in GSK3B modulation of ethanol consumption. Finally, Aim 4 will investigate the
long-term efficacy and potential end-organ toxicity of Tideglusib, a highly specific inhibitor of
GSK3B shown in preliminary studies to decrease ethanol consumption in rodent models.
Tideglusib is already approved for phase II clinical trials on disorders such as autism. Together,
these studies are highly significant and novel, and will provide needed knowledge regarding the
mechanisms of GSK3B modulation of ethanol consumption. This work may also implicate a new
agent, tideglusib, for clinical studies on treatment of AUD.

## Key facts

- **NIH application ID:** 10003129
- **Project number:** 5R01AA027581-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** MICHAEL F MILES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $314,381
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003129

## Citation

> US National Institutes of Health, RePORTER application 10003129, Gsk3b in ethanol consumption and as a therapeutic target for alcohol use disorder (5R01AA027581-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10003129. Licensed CC0.

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