Prior alcohol use enhances vulnerability to compulsive cocaine self-administration by promoting degradation of HDAC4 and HDAC5
| Autor: | Yang Li, Denise B. Kandel, Kimberly A. Kempadoo, Luca Colnaghi, Eric R. Kandel, Philippe A. Melas, Royce Zhou, Edmund A. Griffin, Mei-Chen Hu, Peter Mercado, Stacy Stephenson, Kathleen M. Taylor |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Proteasome Endopeptidase Complex media_common.quotation_subject Drug-Seeking Behavior Self Administration Nucleus accumbens Pharmacology Histone Deacetylases Nucleus Accumbens Epigenesis Genetic Histones Rats Sprague-Dawley Nicotine 03 medical and health sciences Reward system 0302 clinical medicine Cocaine mental disorders Animals Medicine Research Articles media_common Histone deacetylase 5 Multidisciplinary business.industry Addiction Brain SciAdv r-articles medicine.disease Rats 3. Good health Histone Deacetylase Inhibitors Substance abuse 030104 developmental biology Alcohols Compulsive behavior Proteolysis medicine.symptom Self-administration business 030217 neurology & neurosurgery Research Article Neuroscience medicine.drug |
| Zdroj: | Science Advances |
| ISSN: | 2375-2548 |
| DOI: | 10.1126/sciadv.1701682 |
| Popis: | Prior alcohol use increases vulnerability to cocaine addiction by promoting degradation of HDAC4 and HDAC5. 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. |
| Databáze: | OpenAIRE |
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