Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking

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-releva...

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Published in:Science (American Association for the Advancement of Science) Vol. 368; no. 6487; p. 197
Main Authors: Lepack, Ashley E, Werner, Craig T, Stewart, Andrew F, Fulton, Sasha L, Zhong, Ping, Farrelly, Lorna A, Smith, Alexander C W, Ramakrishnan, Aarthi, Lyu, Yang, Bastle, Ryan M, Martin, Jennifer A, Mitra, Swarup, O'Connor, Richard M, Wang, Zi-Jun, Molina, Henrik, Turecki, Gustavo, Shen, Li, Yan, Zhen, Calipari, Erin S, Dietz, David M, Kenny, Paul J, Maze, Ian
Format: Journal Article
Language:English
Published: United States 10.04.2020
Subjects:
Animals
Cocaine - adverse effects
Cocaine-Related Disorders - genetics
Cocaine-Related Disorders - metabolism
Cocaine-Related Disorders - psychology
Dopamine - metabolism
Dopaminergic Neurons - metabolism
Drug-Seeking Behavior
Gene Expression Regulation
Glutamine - metabolism
Histones - metabolism
Humans
Male
Mice
Mice, Inbred C57BL
Neuronal Plasticity
Nucleus Accumbens - metabolism
Rats
Rats, Sprague-Dawley
Synaptic Transmission
Ventral Tegmental Area - metabolism
ISSN:1095-9203, 1095-9203
Online Access:Get more information
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Summary: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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ISSN:1095-9203
1095-9203
DOI:10.1126/science.aaw8806