Micro RNA Implicated as Molecular Factor in Alcohol Tolerance

In recent years, a class of small molecules known as microRNAs have been found to play an important role in regulating gene products in most animal and plant species. A new study now indicates that microRNA may influence the development of alcohol tolerance, a hallmark of alcohol abuse and dependence. Researchers supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health, report the findings in the July 31, 2008 issue of the journal Neuron.

"This is an important contribution to efforts aimed at identifying the molecular bases of alcohol tolerance," notes NIAAA Director Ting-Kai Li, M.D.

Tolerance is the decrease in sensitivity to alcohol that develops with both single and repeated exposures to alcohol over time. Individuals who develop high tolerance (low sensitivity) to alcohol are at increased risk for becoming alcohol dependent. Thus, an important research objective has been to identify the adaptations within individual molecules that underlie tolerance.

In previous experiments conducted in rats, Steven N. Treistman, Ph.D., and colleagues at the University of Massachusetts Medical School determined that a brain cell membrane structure known as the BK channel, which is responsible for movement of calcium and potassium from inside to outside a cell, develops tolerance on exposure to alcohol, particularly in two brain regions important in alcohol's effects (the supraoptic nucleus and the striatum). In both regions, alcohol tolerance was manifested as decreased alcohol sensitivity and a reduced number of BK channels. Previous studies have also shown that there are numerous variants of the BK channel gene.

In the current study, researchers led by Dr. Treistman, Professor of Psychiatry and Director of the Brudnick Neuropsychiatric Research Institute at the University of Massachusetts Medical School in Worcester , MA, examined whether microRNA might be involved in the alcohol tolerance observed in the BK channel.

The researchers showed that the amount of a specific microRNA molecule known as miR-9 increases in brain cells within minutes of exposure to alcohol. The increase in miR-9 causes a reduction in the number of BK channels that contain the specific binding site for miR-9, while sparing those that lack it. Remarkably, the BK channels that were destroyed exhibited high alcohol sensitivity, while those that remained showed significantly lower sensitivity, consistent with the development of tolerance.

"This represents a novel mechanism by which neurons are able to adapt to alcohol," said Dr. Treistman. "Moreover, since adaptation (or tolerance) to the drug likely contributes to alcohol abuse, our findings identify a potential molecular target for therapeutic intervention. It is important to acknowledge a major contribution by my colleagues, especially Dr. Andre Pietrzykowski in this work."

Dr. Treistman adds that the microRNA process observed in this study may represent a general mechanism of neuronal adaptation to alcohol, with miR-9 playing a pivotal role in a complex regulatory network.

"This study demonstrates for the first time that alcohol exposure can cause rapid changes in microRNA levels, altering gene expression, and perhaps behavior," added Antonio Noronha, Ph.D., director of NIAAA’s Division of Neuroscience and Behavior. "In future studies, it will be interesting to determine if similar microRNA-based regulatory mechanisms influence alcohol problems in human populations."

This study was also supported by the Alcoholic Beverage Medical Research Foundation.

The National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems and disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at www.niaaa.nih.gov.