Cocaine Self-Administration Alters Gene Expression

November 22, 1996

Media contact: Kate Egan
from 11/16-11/20, 301-656-7490
Emory University

WASHINGTON, D.C. -- Scientists at Yerkes Primate Research Center of Emory University reveal at this week`s Society for Neuroscience meeting that cocaine significantly alters the activity of nearly 20 genes in the brain, many of which have never before been identified. Such changes at the genetic level may have serious and long-lasting consequences, the implications of which are still not fully understood.

Animal studies by neuroscientist Pastor Couceyro, Ph.D., showed that the differences in genetic activity appear in the three discrete areas of the rat brain which have for several years been thought to be associated with drug addiction.

One of the genes that changed significantly in response to cocaine is a previously-characterized gene called nicotinamide adenine dinucleotide dehydrogenase (NADH), which produces an enzyme crucial in generating cellular energy. The changes occur during the process called transcription, a vital step in the production of an enzyme. To synthesize a working enzyme, DNA`s genetic information must first be transcribed into RNA. Cocaine administration alters dramatically the amount of RNA that is transcribed from DNA in these three specific brain regions. This is the first report of this gene or its encoded enzyme being affected by any drug of abuse.

Previous research on addiction has focused on the effect of drug use on the brain levels of various neurotransmitters, the proteins that produce them, and cell-surface proteins such as neurotransmitter receptors and transporters. Recently, Dr. Couceyro`s lab and others have gone a step further to examine how the genes themselves are affected.

Says Dr. Couceyro, "Our approach to studying drugs of abuse represents a departure from previous strategies in two ways: our gene screening method and our animal model." To determine which genes might be affected by cocaine, he and his team used a special screening technique called differential display polymerase chain reaction (ddPCR), which allowed them to examine the normal RNA activity of numerous genes from various brain areas simultaneously, and to study their response to treatments of cocaine. They then applied ddPCR to one of the most powerful tools in addiction studies--the rat cocaine self-administration model. In this model, the animal rather than the investigator controls delivery of the drug, thus closely mimicking the human pattern of drug abuse.

Using ddPCR, Dr. Couceyro compared the RNA in several brain areas from control and cocaine-treated animals. He found numerous genes that are altered by drugs such as cocaine--but further research is required to determine specifically how these changes might contribute to addiction. "The fact that we discovered many new genes that react to cocaine attests to the complex nature of drug addiction and reinforces the notion that a single gene or gene defect does not bear sole responsibility for this widespread disease," explains Couceyro.

This study was inspired by Dr. Couceyro`s previous work with ddPCR, which helped to identify a new gene called CART, whose levels increased rapidly in the brain following intake of cocaine or amphetamine. "We suspect that this protein may be a previously unidentified chemical transmitter in the brain. Our current studies are evaluating this hypothesis."

The Yerkes Primate Research Center of Emory University is a leading scientific center in biomedical and behavioral investigation, with studies conducted by researchers from Emory and scientific institutions throughout the world.
Kate Egan

Emory University Health Sciences Center

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