2. Academic Validation
  3. Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking

Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking

  • Science. 2020 Apr 10;368(6487):197-201. doi: 10.1126/science.aaw8806.
Ashley E Lepack 1,  Craig T Werner 2,  Andrew F Stewart 1,  Sasha L Fulton 1,  Ping Zhong 3,  Lorna A Farrelly 1,  Alexander C W Smith 1,  Aarthi Ramakrishnan 1,  Yang Lyu 1,  Ryan M Bastle 1,  Jennifer A Martin 2,  Swarup Mitra 2,  Richard M O'Connor 1,  Zi-Jun Wang 3,  Henrik Molina 4,  Gustavo Turecki 5,  Li Shen 1,  Zhen Yan 3,  Erin S Calipari 6,  David M Dietz 2,  Paul J Kenny 1,  Ian Maze 7 8
Affiliations

Affiliations

  • 1 Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 2 Department of Pharmacology and Toxicology, Program in Neuroscience, State University of New York at Buffalo, Buffalo, NY 14214, USA.
  • 3 Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA.
  • 4 Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA.
  • 5 Department of Psychiatry, McGill University, Montreal, QC H3A 1A1, Canada.
  • 6 Department of Pharmacology, Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 7 Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. ian.maze@mssm.edu.
  • 8 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
PMID: 32273471 DOI: 10.1126/science.aaw8806
Abstract

Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from the rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in the midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in the VTA. By reducing H3Q5dop in the VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in the VTA.

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