RESEARCHERS IDENTIFY BRAIN PROTEINS TARGETED BY ALCOHOLS AND OTHER ANESTHETICS
08 August 2000 - University of Texas at Austin

This discovery not only could lead to the development of new drugs for the treatment of alcoholism, but also to improvements in anesthetics, the researchers said.

Dr. R. Adron Harris, director of the UT Austin Waggoner Center for Alcohol and Addiction Research, and his colleagues have been able to pin down the activity of the two drugs in the body for the first time by using an innovative approach outlined in the August issue of the Proceedings of the National Academy of Sciences.

Harris holds the M. June and J. Virgil Waggoner Chair in Molecular Biology. His collaborators were Dr. Maria Paola Mascia, a research associate with the Waggoner Center, and Dr. James R. Trudell, professor of chemistry in anesthesia at Stanford University.

While alcohols and other anesthetics are widely used in modern society, their activities within the human body have largely remained a mystery. Harris said scientists previously believed that alcohols and anesthetics worked differently than other drugs because alcohol must be consumed in much larger quantities to have the same effects.

"For example, because you would have to drink so much more alcohol than the amount of Valium you would take, the argument was that the two substances must be working in fundamentally different ways," he explained. "We know that Valium works on specific protein-binding sites. So, for a long time, the idea was that alcohols and anesthetics must be different. Maybe the alcohols didn't even act on proteins at all."

Another reason that researchers were unable to learn more about alcohols and anesthetics was because both these substances act so quickly.

"They can go on and off their binding sites very rapidly," Harris said. "They don't stick like Prozac or Valium. Since the techniques that have been used to understand the targets of most other drugs wouldn't work, we had to devise a different approach."

The researchers decided to use sulfur to force the molecules of alcohol and anesthetics to bind to their target sites on the brain proteins, basically acting like a glue.

"We introduced a sulfur into the anesthetic, and we introduced a sulfur onto the receptor," Harris said. "Those two sulfurs formed a chemical bond that stuck the anesthetic to the receptor. We had the thing trapped. We could study what it did at our leisure because it was permanently attached."

Harris said that sulfur can be introduced into all the proteins in the brain to identify protein-binding sites. He said this same process may work for any drug.

Harris also said the research opens up the possibility "of designing better anesthetics with fewer side effects. There is also the possibility of designing drugs that will interfere with the action of alcohol in the brain, which might be useful for treatment of alcoholism. Just as methadone is a drug like an opiate that is useful in treating opiate addiction, it may be possible to design some new kinds of drugs that are useful in treating alcohol addiction."

Harris and his colleagues looked for the alcohol and anesthetic-binding sites of two specific proteins called glycine and Gamma-aminobutyric acid [or GABA(A)], that control electrical activity and, therefore, nerve activity in the brain. These proteins normally help to form a balance between electrical, or nervous, excitation and inhibition.

"You have to balance the excitation in the brain with inhibition. You have to have the gas pedal and the brake pedal," Harris explained. "The excitatory ones are the gas pedal, and the GABA(A) and glycine are the brake pedal. They control the firing rates of the nerves in the brain." He said the way anesthetics enhance inhibition, and alcohols increase sedation, disinhibition and other reactions, is by largely targeting the GABA(A) and glycine proteins. Researchers at the Waggoner Center currently are examining other proteins for alcohol and anesthetic-binding sites.

The research was funded by the National Institute on Alcohol Abuse and Alcoholism, the National Institute of General Medical Sciences and the Texas Commission on Alcohol and Drug Abuse.

The interdisciplinary UT Austin Waggoner Center for Alcohol and Addiction Research was founded in 1998 through a gift from the M. June and J. Virgil Waggoner Foundation to investigate the molecular basis of nerve cell sensitivity to alcohol and other anesthetics

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