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

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.

• Authors: Edmund A Griffin Jr, Philippe A Melas, Royce Zhou, Yang Li, Peter Mercado, Kimberly A Kempadoo, Stacy Stephenson, Luca Colnaghi, Kathleen Taylor, Mei-Chen Hu, Eric R Kandel, Denise B Kandel
• Journal: Science advances (Sci Adv) Vol. 3 Issue 11 Pg. e1701682 (11 2017) ISSN: 2375-2548 [Electronic] United States
• PMID: 29109977 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Alcohols
• Histone Deacetylase Inhibitors
• Histones
• Proteasome Endopeptidase Complex
• HDAC4 protein, rat
• Hdac5 protein, rat
• Histone Deacetylases
• Cocaine

Topics

• Alcohols (pharmacology)
• Animals
• Brain (pathology)
• Cocaine (pharmacology)
• Drug-Seeking Behavior (drug effects)
• Epigenesis, Genetic (drug effects)
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases (chemistry, metabolism)
• Histones (metabolism)
• Nucleus Accumbens (drug effects, metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Proteolysis (drug effects)
• Rats
• Rats, Sprague-Dawley
• Self Administration