Affordable Access

Publisher Website

Transcriptional Dysregulation of Cholesterol Synthesis Underlies Hyposensitivity to GABA in the Ventral Tegmental Area During Acute Alcohol Withdrawal.

Authors
  • You, Chang1
  • Krishnan, Harish R2
  • Chen, Ying2
  • Zhang, Huaibo2
  • Drnevich, Jenny3
  • Pinna, Graziano2
  • Guidotti, Alessandro2
  • Glover, Elizabeth J2
  • Lasek, Amy W2
  • Grayson, Dennis R2
  • Pandey, Subhash C4
  • Brodie, Mark S5
  • 1 Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois; Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois.
  • 2 Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois.
  • 3 Roy J. Carver Biotechnology Center, University of Illinois at Urbana-Champaign, Urbana, Illinois.
  • 4 Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois; Jesse Brown VA Medical Center, Chicago, Illinois.
  • 5 Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois; Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois. Electronic address: [email protected].
Type
Published Article
Publication Date
Feb 01, 2024
Volume
95
Issue
3
Pages
275–285
Identifiers
DOI: 10.1016/j.biopsych.2023.07.018
PMID: 37562519
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The ventral tegmental area (VTA) is a dopaminergic brain area that is critical in the development and maintenance of addiction. During withdrawal from chronic ethanol exposure, the response of VTA neurons to GABA (gamma-aminobutyric acid) is reduced through an epigenetically regulated mechanism. In the current study, a whole-genome transcriptomic approach was used to investigate the underlying molecular mechanism of GABA hyposensitivity in the VTA during withdrawal after chronic ethanol exposure. We performed RNA sequencing of the VTA of Sprague Dawley male rats withdrawn for 24 hours from a chronic ethanol diet as well as sequencing of the VTA of control rats fed the Lieber-DeCarli diet. RNA sequencing data were analyzed using weighted gene coexpression network analysis to identify modules that contained coexpressed genes. Validation was performed with quantitative polymerase chain reaction, gas chromatography-mass spectrometry, and electrophysiological assays. Pathway and network analysis of weighted gene coexpression network analysis module 1 revealed a significant downregulation of genes associated with the cholesterol synthesis pathway. Consistent with this association, VTA cholesterol levels were significantly decreased during withdrawal. Chromatin immunoprecipitation indicated a decrease in levels of acetylated H3K27 at the transcriptional control regions of these genes. Electrophysiological studies in VTA slices demonstrated that GABA hyposensitivity during withdrawal was normalized by addition of exogenous cholesterol. In addition, inhibition of cholesterol synthesis produced GABA hyposensitivity, which was reversed by adding exogenous cholesterol to VTA slices. These results suggest that decreased expression of cholesterol synthesis genes may regulate GABA hyposensitivity of VTA neurons during alcohol withdrawal. Increasing cholesterol levels in the brain may be a novel avenue for therapeutic intervention to reverse detrimental effects of chronic alcohol exposure. Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Report this publication

Statistics

Seen <100 times