Transcriptional Mechanisms Of Drug Addiction
Air date: Wednesday, May 06, 2009, 3:00:00 PM
Description: Addiction can be viewed as a form of drug-induced neural plasticity. Given the stability of the behavioral abnormalities that characterize an addicted state, it makes sense that stable changes in gene expression are involved. Among several transcriptional mechanisms implicated in drug addiction, our laboratory has focused on two main pathways.
First, chronic exposure to cocaine or certain other drugs of abuse causes prolonged activation of the transcription factor CREB within several brain regions, and this adaptation mediates aspects of tolerance and dependence. In contrast, induction of another transcription factor, termed ?FosB, in some of the same brain regions exerts the opposite effect and contributes to sensitized responses to drug exposure. Studies are underway to explore the detailed molecular mechanisms by which CREB and FosB regulate target genes and thereby contribute to the complex state of addiction. One way to approach such molecular mechanisms of drug action in vivo is through the study of chromatin remodeling, that is, changes in the acetylation or methylation of histones that bind to certain drug-regulated gene promoters, or changes in methylation of the promoters themselves, as revealed by chromatin immunoprecipitation (ChIP).
We are utilizing ChIP to examine chromatin changes at specific candidate genes for CREB and ?FosB, as well as ChIP on chip (immunoprecipitated chromatin analyzed by gene promoter arrays) to gain a global view of target genes for these transcription factors. We are also investigating drug regulation of some of the enzymes that catalyze chromatin remodeling as additional drug targets.
These findings establish chromatin remodeling as an important regulatory mechanism underlying drug-induced neural and behavioral plasticity, and promise to reveal fundamentally new insight into how CREB and ?FosB, and several other transcription factors, contribute to addiction by regulating the expression of specific target genes.
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Author: Nestler, Eric J.
National Institutes of Health (U.S.)