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Prior alcohol use enhances vulnerability to compulsive cocaine self-administration by promoting degradation of HDAC4 and HDAC5

Edmund Griffin Jr.; Philippe Melas; Royce Zhou; Yang Li; Peter Mercado; Kimberly Kempadoo; Stacy Stephenson; Luca Colnaghi; Kathleen M. Taylor; Mei-Chen Hu; Eric Kandel; Denise B. Kandel

Title:
Prior alcohol use enhances vulnerability to compulsive cocaine self-administration by promoting degradation of HDAC4 and HDAC5
Author(s):
Griffin Jr., Edmund
Melas, Philippe
Zhou, Royce
Li, Yang
Mercado, Peter
Kempadoo, Kimberly
Stephenson, Stacy
Colnaghi, Luca
Taylor, Kathleen M.
Hu, Mei-Chen
Kandel, Eric
Kandel, Denise B.
Date:
Type:
Articles
Department(s):
Neuroscience
Psychiatry
Sociomedical Sciences
Volume:
3
Persistent URL:
Book/Journal Title:
Science Advances
Abstract:
Addiction to cocaine is commonly preceded by experiences with legal or decriminalized drugs, such as alcohol, nicotine, and marijuana. The biological mechanisms by which these gateway drugs contribute to cocaine addiction are only beginning to be understood. We report that in the rat, prior alcohol consumption results in enhanced addiction-like behavior to cocaine, including continued cocaine use despite aversive consequences. Conversely, prior cocaine use has no effect on alcohol preference. Long-term, but not short-term, alcohol consumption promotes proteasome-mediated degradation of the nuclear histone deacetylases HDAC4 and HDAC5 in the nucleus accumbens, a brain region critical for reward-based memory. Decreased nuclear HDAC activity results in global H3 acetylation, creating a permissive environment for cocaine-induced gene expression. We also find that selective degradation of HDAC4 and HDAC5, facilitated by the class II–specific HDAC inhibitor MC1568, enhances compulsive cocaine self-administration. These results parallel our previously reported findings that the gateway drug nicotine enhances the behavioral effects of cocaine via HDAC inhibition. Together, our findings suggest a shared mechanism of action for the gateway drugs alcohol and nicotine, and reveal a novel mechanism by which environmental factors may alter the epigenetic landscape of the reward system to increase vulnerability to cocaine addiction.
Subject(s):
Cocaine abuse
Substance abuse
Compulsive behavior
Histone deacetylase
Neurosciences
Psychiatry
Publisher DOI:
https://doi.org/10.1126/sciadv.1701682
Item views
13
Metadata:
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Suggested Citation:
Edmund Griffin Jr., Philippe Melas, Royce Zhou, Yang Li, Peter Mercado, Kimberly Kempadoo, Stacy Stephenson, Luca Colnaghi, Kathleen M. Taylor, Mei-Chen Hu, Eric Kandel, Denise B. Kandel, , Prior alcohol use enhances vulnerability to compulsive cocaine self-administration by promoting degradation of HDAC4 and HDAC5, Columbia University Academic Commons, .

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