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Concept
Epigenetics of cocaine addiction
Résumé
Cocaine addiction is the compulsive use of cocaine despite adverse consequences. It arises through epigenetic modification (e.g., through HDAC, sirtuin, and G9a) and transcriptional regulation (primarily through ΔFosB's AP-1 complex) of genes in the nucleus accumbens.
Histone deacetylase inhibitors (HDAC inhibitors) have been implicated as a potential treatment for cocaine addicts. HDACs are enzymes that can deacetylate the histones associated with genes. This can activate genes for transcription. Several experiments have shown that inhibiting HDACs involved in histone H3K9 deacetylation reduces drug seeking behavior.
It has been known that epigenetic regulations, such as the methylation of H3K9, have a key role in the mechanism of addiction. Recent studies have shown that administering HDAC inhibitors can help reduce the craving for cocaine in rats. Trichostatin A (TsA) is an HDAC inhibitor associated with reduced cocaine-seeking behaviors; it inhibits HDAC classes 1, 3, 4, 6, and 10. Since this HDAC inhibitor has such a significant effect on cocaine-seeking behaviors, scientists have speculated about their ability to reduce a person who is addicted to cocaine's risk of relapse in the rat model system during rehab.
After several tests in which rats were exposed to cocaine followed by either an HDAC inhibitor or a placebo, it was found that HDAC inhibitors had a significant effect on lowering cocaine-seeking behavior. This also suggests an epigenetic mechanism involved in HDAC chromatin regulation. The data is crucial to proving the hypothesis that trichostatin A can remodel chromatin structure and prevent behavioral changes following cocaine exposure. Tests also revealed that HDAC inhibitor administration can not only prevent addiction but also helps reduce the risk of relapse in cocaine addicts in the rat model system.
As the previous findings suggest, chronic cocaine use caused both alterations in the chromatin remodeling activity of HDACs and drug-seeking behavior. Renthal et al.
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