Nestler Eric J
Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA.
Philos Trans R Soc Lond B Biol Sci. 2008 Oct 12;363(1507):3245-55. doi: 10.1098/rstb.2008.0067.
Regulation of gene expression is considered a plausible mechanism of drug addiction, given the stability of behavioural abnormalities that define an addicted state. Among many transcription factors known to influence the addiction process, one of the best characterized is DeltaFosB, which is induced in the brain's reward regions by chronic exposure to virtually all drugs of abuse and mediates sensitized responses to drug exposure. Since DeltaFosB is a highly stable protein, it represents a mechanism by which drugs produce lasting changes in gene expression long after the cessation of drug use. Studies are underway to explore the detailed molecular mechanisms by which DeltaFosB regulates target genes and produces its behavioural effects. We are approaching this question using DNA expression arrays coupled with the analysis of chromatin remodelling--changes in the posttranslational modifications of histones at drug-regulated gene promoters--to identify genes that are regulated by drugs of abuse via the induction of DeltaFosB and to gain insight into the detailed molecular mechanisms involved. Our findings establish chromatin remodelling as an important regulatory mechanism underlying drug-induced behavioural plasticity, and promise to reveal fundamentally new insight into how DeltaFosB contributes to addiction by regulating the expression of specific target genes in brain reward pathways.
鉴于定义成瘾状态的行为异常具有稳定性，基因表达调控被认为是药物成瘾的一种合理机制。在已知影响成瘾过程的众多转录因子中，特征最明显的之一是DeltaFosB，它在大脑奖赏区域中由长期接触几乎所有滥用药物诱导产生，并介导对药物接触的敏感反应。由于DeltaFosB是一种高度稳定的蛋白质，它代表了一种机制，通过这种机制，药物在停止使用后很长时间仍能在基因表达上产生持久变化。目前正在进行研究，以探索DeltaFosB调节靶基因并产生其行为效应的详细分子机制。我们正在通过使用DNA表达阵列结合染色质重塑分析——药物调节基因启动子处组蛋白翻译后修饰的变化——来解决这个问题，以识别通过DeltaFosB的诱导而受滥用药物调节的基因，并深入了解其中涉及的详细分子机制。我们的研究结果将染色质重塑确立为药物诱导行为可塑性的重要调节机制，并有望揭示DeltaFosB如何通过调节大脑奖赏通路中特定靶基因的表达而导致成瘾的全新见解。
