Neurosteroids: the missing link?

December 13, 1999

A natural brain compound called a neurosteroid may be the missing link between alcohol and a major neurotransmitter called gamma-aminobutyric acid (GABA). Alcohol's effects on GABA receptors in the brain were know to cause the relaxing, sedative, anticonvulsant and intoxicating effects of alcohol but, until recently, researchers didn't know exactly how. Now they believe, as outlined in the December issue of Alcoholism: Clinical & Experimental Research, they have found the missing piece of the puzzle.

"Neurosteroids are steroid compounds that are called neurosteroids for two reasons," said A. Leslie Morrow, associate professor of psychiatry and pharmacology as well as associate director of the Center for Alcohol Studies at the University of North Carolina School of Medicine. "One reason is that they are synthesized in the brain and two, they are very, very fast modulators of receptors for neurotransmitters."

Steroids and neurosteroids are very different from one another. Steroids are a class of natural and synthetic organic chemical compounds characterized by a particular molecular structure. They include the sex hormones, adrenal cortical hormones, bile acids, sterols, anabolic agents, and oral contraceptives. Most people recognize anabolic steroids, a synthetic version of the male sex hormone called testosterone. Neurosteroids are brain chemicals. Unlike most of the body's potent steroids, which are made in the sex glands, neurosteroids are only synthesized in the brain. Neurosteroids are known to be involved in behavior, stress, memory, depression, anxiety, aging of the brain, and neurodegenerative diseases. Relatively speaking, neurosteroids are the proverbial new kid on the block, only recognized in the last 10 or 15 years.

"Most hormonal-type steroids produce their effects over time by altering gene expression in the nucleus of the cell," said Morrow, first author of the symposium proceedings. "This might occur over hours or days. Neurosteroids produce their effects by interacting with neurotransmitter receptors and then altering neurotransmission, producing their effects in a millisecond time frame."

"There are two major neurotransmitters in the brain," said Richard A. Morrisett, associate professor of pharmacology at The University of Texas at Austin. "These are glutamate and GABA. Glutamate is the accelerator pedal and GABA is the brake pedal. GABA essentially shuts the brain off." Morrisett explained that neurochemists and electrophysiologists were at odds for almost 20 years because one group believed that alcohol strongly activated GABA function while the other group disagreed. "It's now thought that alcohol increases the brain level of neurosteroids, which then increase GABA function."

Referring again to his automobile analogy, Morrisett said that "glutamate is the gas pedal, GABA is the brake and neurosteroids act like brake fluid. When you hit the brake, neurosteroids are going to control how strong the brakes are actually applied. So if you increase neurosteroid levels, which is what alcohol seems to do, then the brakes are applied even stronger.

According to Morrow, the sites of alcohol action in the brain have been disputed for a long time and are still not completely understood. However, the five studies collected for the symposium paper suggest that alcohol's effects on neurosteroids have a major role in alcohol's effects on the brain. Future work will no doubt focus on what modulating role neurosteroids are playing relative to alcohol

"These findings are both significant and pretty recent," said Morrisett. "We've known about neurosteroids for at least a decade, but only about their relationship to alcohol for the last couple of years. Now we have to define the question before we can even begin to answer it. For this field, that is about as 'cutting edge' as you can get."

Co-authors of the Alcoholism: Clinical & Experimental Research symposium proceedings included: Gregory C. Janis of the Departments of Psychiatry and Pharmacology and Center for Alcohol Studies at the University of North Carolina and the Department of Pharmacology at the Boston University Medical Center, Margaret J. VanDoren of the Departments of Psychiatry and Pharmacology, Curriculum in Neurobiology, and Center for Alcohol Studies at the University of North Carolina, Douglas B. Matthews of the Departments of Psychiatry and Pharmacology and Center for Alcohol Studies at the University of North Carolina and the University of Memphis, Herman H. Samson and Kathleen A. Grant of the Center for the Neurobehavioral Study of Alcohol, Department of Physiology and Pharmacology at Wake Forest University School Medicine, and Patricia H. Janak of the Center for the Neurobehavioral Study of Alcohol, Department of Physiology and Pharmacology at Wake Forest University School Medicine and the National Institute of Drug Abuse.

The studies were funded in part by the National Institute of Alcohol Abuse and Alcoholism and the National Science Foundation.
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Alcoholism: Clinical & Experimental Research

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