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December 11, 2000

Hemby's study dusts cocaine addiction for prints

By Poul Olson

Researchers led by Yerkes’ Scott Hemby have identified more than 400 human genes affected by long-term cocaine abuse. The discovery, reported at the recent Society for Neuroscience annual meeting in New Orleans, represents the first molecular profile, or “fingerprint,” for human drug addiction and ultimately could lead to new treatments for addiction.

Applying DNA microarray technology, the most powerful method for gene expression profiling, Hemby analyzed brain tissue from 10 human subjects who had overdosed on cocaine and an equal number of controls. Among the 9,000 genes scrutinized per subject, more than 400 turned out to have become disregulated—turned either on or off—due to long-term cocaine use.

“For the first time, we have looked at a portion of the human genome and determined the effects of a drug like cocaine,” said Hemby, director of the Emory DNA Microarray Facility and an assistant professor of pharmacology. “It’s going to take a long time to work this out, but we’re setting up a framework that we can take into studies of opiate and alcohol addiction and other human diseases that will ultimately lead to the development of new treatments.”

The identification of genetic markers for addiction could be the most significant advance in drug addiction research in decades. Much of the work was made possible by the recent development of DNA microarray technology, which enabled the simultaneous assessment of thousands of genes. Hemby noted the tool has been a boon for researchers who study complex mammalian behaviors dictated by coordinate changes in gene expression of many genes.

Identifying genes associated with cocaine addiction has been constrained by the limitations of conventional gene expression profiling, which can only focus on single genes. One of the greatest successes in identifying genes associated with cocaine use was the characterization by Yerkes’ Mike Kuhar of Cocaine and Methamphetamine Transcript (CART).

In addition to analyzing many genes simultaneously, DNA microarray technology can identify genes whose functions are either known or unknown. The complex process begins with the fabrication of a “gene chip” made up of DNA copies derived from more than 40,000 human genes.

With the human genome now completely mapped, Hemby hopes to soon have access to a complete library from which to make gene chips. Given the number of genes already identified, he expects to find several more disregulated genes involved in cocaine addiction. He noted that while finding the disregulated genes has marked a significant advance, equally important is identifying those that remain unchanged by long-term cocaine use.

Hemby’s research opens several new frontiers in drug addiction research. Conven-tional drug addiction studies have attempted to use animals to model this uniquely human condition, with its myriad molecular processes that cannot be accurately reproduced in the laboratory.

While many researchers continue to focus on identifying brain receptors for drugs, Hemby said mounting evidence clearly shows that genes form the biological underpinnings for addiction.

“Addiction research generally has taken a global approach to understanding how a drug like cocaine affects the brain,” Hemby said. “Conven-tional tests, such as functional MRIs, provide a broad measure of what is taking place during drug self-administration. But it doesn’t give us a panel of things that are changing.”

This is not to say, however, that Hemby believes drug addiction should be investigated solely at the molecular level. Given the undeniably crucial role of human behavior in the addiction process, Hemby and his collaborator, Deborah Mash, a professor of neurology at the University of Miami, are taking a novel approach to describing the complete spectrum of the addiction process.

Through interviews with the family and friends of cocaine users who died from overdose, Mash conducted “psychological autopsies” of the users. She and Hemby hope to find connections between cocaine users’ genetic profiles and their lifestyles.

Needless to say, this approach is more problematic with animal models. However Hemby is developing a gene expression model in rats for the molecular changes that take place with long-term cocaine use.

We’re asking about what effects are produced at the initial exposure to cocaine, 30 days later and after years of exposure,” Hemby said. “We also want to know what happens when an addict relapses.”

As scientists achieve greater understanding of the biology of cocaine addiction, they hope to develop medications that effectively treat addiction without serious side effects. These medications would target specific aspects of the biochemical pathways that promote a craving for cocaine. The National Institute on Drug Abuse has made it a national priority to develop a therapeutic substitute for cocaine, corresponding to the heroin substitute methadone.

Hemby cautioned that it may not be possible to wholly conquer addiction. “It isn’t reasonable to believe that we can ‘cure’ cocaine addicts,” he said. “Any therapeutic approach should instead be designed to prevent relapse.”


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