Glycogen synthase kinase 3 beta regulates ethanol consumption and is a risk factor for alcohol dependence

and the COGA Consortium

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Understanding how ethanol actions on brain signal transduction and gene expression lead to excessive consumption and addiction could identify new treatments for alcohol dependence. We previously identified glycogen synthase kinase 3-beta (Gsk3b) as a member of a highly ethanol-responsive gene network in mouse medial prefrontal cortex (mPFC). Gsk3b has been implicated in dendritic function, synaptic plasticity and behavioral responses to other drugs of abuse. Here, we investigate Gsk3b in rodent models of ethanol consumption and as a risk factor for human alcohol dependence. Stereotactic viral vector gene delivery overexpression of Gsk3b in mouse mPFC increased 2-bottle choice ethanol consumption, which was blocked by lithium, a known GSK3B inhibitor. Further, Gsk3b overexpression increased anxiety-like behavior following abstinence from ethanol. Protein or mRNA expression studies following Gsk3b over-expression identified synaptojanin 2, brain-derived neurotrophic factor and the neuropeptide Y Y5 receptor as potential downstream factors altering ethanol behaviors. Rat operant studies showed that selective pharmacologic inhibition of GSK3B with TDZD-8 dose-dependently decreased motivation to self-administer ethanol and sucrose and selectively blocked ethanol relapse-like behavior. In set-based and gene-wise genetic association analysis, a GSK3b-centric gene expression network had significant genetic associations, at a gene and network level, with risk for alcohol dependence in humans. These mutually reinforcing cross-species findings implicate GSK3B in neurobiological mechanisms controlling ethanol consumption, and as both a potential risk factor and therapeutic target for alcohol dependence.

Original languageEnglish (US)
JournalNeuropsychopharmacology
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

Fingerprint

Alcoholism
Ethanol
Gene Regulatory Networks
Prefrontal Cortex
Neuropeptide Y Receptors
Gene Expression
Glycogen Synthase Kinase 3 beta
Neuronal Plasticity
Viral Genes
Brain-Derived Neurotrophic Factor
Street Drugs
Lithium
Sucrose
Motivation
Rodentia
Signal Transduction
Anxiety
Recurrence
Messenger RNA
Brain

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Glycogen synthase kinase 3 beta regulates ethanol consumption and is a risk factor for alcohol dependence. / and the COGA Consortium.

In: Neuropsychopharmacology, 01.01.2018.

Research output: Contribution to journalArticle

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