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Delving deeper into the machinery of cocaine addiction

Researchers are now understanding in greater detail the molecular machinery underlying the short-term brain changes that produce the high of cocaine, as well as the longer-term changes behind addiction. Their findings offer hope for targeted drugs that can short-circuit that addiction machinery.

In the October 20, 2005, issue of Neuron, researchers led by Eric J. Nestler and Arvind Kumar of The University of Texas Southwestern Medical Center have pinpointed a key molecular mechanism by which genes are switched on in the brain that govern both short-term and long-term effects of cocaine. Such activation is called transcriptional activation because it induces the gene to begin making copies of itself into messenger RNA that trigger protein production.

In their experiments, the researchers studied a process called "chromatin remodeling"--in which the histone proteins enfolding genes are chemically altered to render the genes active. They administered to rats both short-term, acute cocaine doses and long-term, chronic cocaine and analyzed the alteration of the histones affecting specific genes involved in cocaine response in the brain.

In their studies, they used an analytical technique called "chromatin immunoprecipitation assays" to measure the effects of cocaine on histone proteins. This technique, they emphasized, makes it possible "to study such transcriptional mechanisms in the brain in vivo and understand, with increasing complexity, how chronic cocaine administration leads to the long-term regulation of its target genes."

The researchers found that giving the rats acute doses of cocaine induced histone modifications that activated a gene called cFos, which is an important regulator of many other genes. However, this gene was desensitized by chronic cocaine.

In contrast, they found, histone modifications activated two other genes, BDNF and Cdk5, only during chronic cocaine administration. Their findings, they wrote, "direct
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Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press
19-Oct-2005


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