NIH Study Identifies Gene Variant Linked to Compulsive Drinking.

Adolescent binge drinking linked to lower levels of brain-derived neurotrophic factor.

Carrying a gene variant that affects the release of a specific brain protein may put one at greater risk of developing an alcohol use disorder, according to the results of a recent animal study. The study was led by Professor Dorit Ron, PhD, Endowed Chair of Cell Biology of Addiction, Department of Neurology, University of California, San Francisco, and was funded by the National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health.

Scientists found that mice carrying the Met68BDNF gene variant, which reduces the release of brain-derived neurotrophic (BDNF) factor, would consume excessive amounts of alcohol, despite negative consequences. BDNF plays a role in the survival of existing neurons and the growth of new neurons and synapses, the junctures through which cell-to-cell communication occurs. The human form of this gene variant, Met66BDNF, leads to a reduction in the normal function of BDNF in the brain and is associated with several psychiatric disorders, including schizophrenia and depression.

In an animal study reported earlier this year, NIAAA-supported scientists found that adolescent binge drinking was linked to lower levels of brain-derived neurotrophic factor, and these changes persisted into adulthood.

"Genetic factors play a role in determining who develops alcohol problems," said Dr. George Koob, PhD, NIAAA Director. "By understanding the genetic underpinnings of alcohol use disorder, we will be better able to develop targeted treatment and prevention strategies."

In the study, published in Biological Psychiatry, researchers tested the role of BDNF in alcohol addiction by creating a "knock-in" mouse carrying Met68BDNF. In this variant, the amino acid valine (Val) is replaced by methionine (Met) in a specific position within the protein sequence of BDNF, resulting in reduced activity-dependent BDNF release. These "knock-in" mice drank more alcohol, even when the alcohol was treated with bitter-tasting quinine. This suggests Met68BDNF carriers compulsively drink alcohol despite aversive consequences.

The effect of the genetic mutation seemed to be specific to alcohol consumption since the mice did not differ in their consumption of other fluids, or exhibit differences in levels of anxiety or compulsive behaviors

Significantly, researchers were able to reverse compulsive alcohol drinking in the mice using gene delivery and pharmacology. Increasing levels of BDNF in the ventromedial portion of the prefrontal cortex, a brain region involved in compulsive drug and alcohol seeking, returned the mice to moderate levels of alcohol intake.

In addition, by administering a pharmaceutical compound developed to mimic the action of BDNF, researchers were also able to put a stop to compulsive drinking behaviors. This compound (LM22A-4) may have potential as a therapeutic for humans. It appears to reduce compulsive alcohol drinking without a generalized effect on motivation.

Alcohol use disorder affects about 16.6 million adults in the United States. Knowing whether patients carry a gene that results in decreased BDNF function could help in tailoring alcohol prevention and treatment strategies in the future.

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. NIAAA also disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at http://www.niaaa.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.