How and why people become addicted to alcohol

Virginia Commonwealth University researchers have identified several genetic changes in the brains of mice caused by ethanol, which may help researchers better understand how and why people become addicted to alcohol.

In the March issue of the Journal of Neuroscience, researchers reported significant differences in the gene expression patterns regulated by alcohol in two mouse strains known as B6 and D2. The two mouse strains differ in a number of behavioral responses to acute alcohol and in their predisposition to drink alcohol.

Researchers isolated tissue from three different regions of the brain that are all known to play a role in responses to alcohol and other drugs of abuse. Using DNA microarrays, which measure the activity of more than 10,000 genes simultaneously, together with large databases of other biological information, researchers were able to identify several genes regulated by alcohol that may play a role in determining genetic differences in behavioral responses to alcohol.

“These findings help us to better understand the molecular basis for genetic differences in behavioral response to alcohol and may eventually lead to new therapeutic approaches for alcoholism,” said Michael Miles, M.D., Ph.D., a professor in pharmacology, toxicology and neurology, who also has an appointment in VCU Life Sciences’ Center for the Study of Biological Complexity.

Gene expression refers to how much a given gene is “turned on,” eventually leading to more or less protein being produced by that particular gene. Changes in a gene’s expression are thought to be an important mechanism underlying long-term memory and learning, including that which occurs with addiction to alcohol or other drugs, Miles said.

In the study, approximately 400 genes were identified as alcohol regulated in at least one brain region of either mouse strain. According to Miles, most of these genes showed regulation in only one or the other strain, or in some cases exposure to alcohol caused genes to be turned on more in one strain while decreasing expression of the same gene in the other mouse strain. Such differences are thought to be related to the mechanisms underlying the different behaviors that the B6 and D2 mice show with alcohol.

Researchers also determined whether genes with changes in expression had a functional relationship with each other. For example, they determined that many genes regulated by alcohol participated in certain biological pathways, such as the one leading to the production of myelin. Myelin is a form of molecular insulation that allows nerve cells to send impulses to one another more effectively. Such pathways showed different responses to alcohol in one mouse strain versus the other. As a result, Miles and his colleagues were able to formulate new hypotheses about how the brains of the mouse strains responded differently to alcohol.

An additional pathway found to be regulated by alcohol involved a nerve growth factor called Bdnf. Bdnf is found in the brain and is a vital part of nervous system development.

“We found that the interaction between the Bdnf gene and several other genes that interact with Bdnf were all regulated in one region of the brain that is known to play a role in drug addiction,” Miles said. “These findings suggest a ‘network’ of genes that may be a key to understanding drinking behaviors and the mechanisms of alcoholism.”

Other studies have suggested that interfering with Bdnf signaling can alter alcohol consumption.

If researchers can identify drugs that may inhibit or activate the function of one of the genes identified in these studies, they may be able to generate new treatments for alcoholism or addiction, Miles said.

“The genes identified in our studies may eventually lead to other studies that can evaluate an individual’s risk for becoming an alcoholic or suffering certain complications from alcohol,” he said.

Also working on the study were the University of Tennessee Health Sciences; the University of Memphis; the University of Colorado; and the University of California at San Francisco.

This research is supported by grants from the National Institute on Alcohol Abuse and Alcoholism.