Like a computer virus eating away software, chronic alcohol abuse can change the programming of critical areas of the human brain on the molecular level, researchers at The University of Texas at Austin have discovered.

Their research, published in the December issue of Alcoholism: Clinical & Experimental Research (ACER), is the first to use a technique called gene array technology in studying ways alcoholism disrupts important gene mechanisms.

Dr. R. Adron Harris, director of UT Austin's Waggoner Center for Alcohol and Addiction Research and lead author, said: "A critical question in addiction is how the reprogramming of the brain leads to long-lasting, severe, life-threatening dependence. This study provides insight regarding the molecular neuro-circuitry of the frontal cortex that is altered in alcoholism." Harris holds the M. June And J. Virgil Waggoner Chair in Molecular Biology.

Harris said the researchers studied the superior frontal cortex of the brain, a crucial area involving judgment and decision-making. He said these are "tasks that are corrupted in addiction. Just as a computer virus can change the programming of specific functions, our data show that chronic alcohol abuse can change the molecular programming and circuitry of the frontal cortex."

Harris said all cells have exactly the same genes or deoxyribonucleic acid (DNA). Different cells work differently because only some genes are 'turned on' in each cell, a process referred to as gene expression. RNA, or ribonucleic acid, acts as a messenger, translating instructions from DNA into the proteins that determine the appearance and function of each cell. Drugs disrupt this normally well-regulated process.

"Alcohol can change gene expression in the brain. This is believed to be responsible for many of the hallmarks of addiction, such as tolerance, physical dependence and craving, as well as the consequences of chronic alcoholism, such as neurotoxicity (brain damage)," Harris said.

Harris said the challenge has been to find which genes are 'incorrectly' turned on or off in the brains of human alcoholics because any of 50,000 genes may be important. Until the development of gene array technology, it was impossible to analyze more than a handful of these genes.

A gene array is a small glass microscope slide that has thousands of different DNA samples attached to the glass. The new technology can detect expression of thousands of gene products simultaneously.

Researchers measured the level of thousands of RNAs in the brain. RNA samples were extracted from post-mortem samples of superior frontal cortex of 10 alcoholics and 10 non-alcoholics, and were measured by two different types of microarrays (the Affymetrix and Genome systems). Using two microarrays -- a more complicated, challenging and expensive venture than just one -- provided more complete gene coverage and enhanced the reliability of the findings.

Harris said: "RNA can be converted to a complimentary DNA called cDNA with a fluorescent or colored 'tag' that will very selectively bind to, or partner with, its corresponding DNA. We can put a drop of this brain cDNA on the gene array and each spot of DNA that shows a colored tag will indicate that it is a gene that is turned on in the brain. Thus, each gene or DNA element on the array has a color that reflects how much the gene is turned on in the alcoholic relative to the control."

More than 4,000 genes in brain tissue were analyzed simultaneously. Of these, 163 (or roughly 4 percent) were found to differ by 40 percent or more between the alcoholics and non-alcoholics.

The genes that seemed to change were those related to the generation of white matter in the brain, called myelin. The researchers believe this may indicate that alcohol has a particularly damaging effect on the generation of myelin. Myelin forms insulation between information-carrying cells of the brain, and loss of white matter may result in cognitive deficiencies.

These findings not only provide evidence for an extensive reprogramming of brain gene expression due to alcoholism, but also identify several functional clusters of genes that are particularly affected by the disease.

Co-authors include: Dr. Joanne M. Lewohl of the Waggoner Center and the department of biochemistry at the University of Queensland, Australia; Long Wang, Michael F. Miles, and Li Zhang of the Ernest Gallo Clinic and Research Center at the University of California at San Francisco; and Peter R. Dodd of the department of biochemistry at the University of Queensland.

---University of Texas, Austin

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