Mice Lacking Gene Show Reduced Alcohol Preference And Sensitivity

(Portland, OR) -- Researchers at Oregon Health Sciences University and the Portland Veterans Affairs Medical Center are helping reinforce the idea of a genetic basis for alcoholism. New research being published in the November edition of the journal Nature Neuroscience shows that laboratory mice bred without a functional gene associated with the brain's reward system have a lower preference for and sensitivity to alcohol than their counterparts who have the gene. The research was funded by the U.S. Department of Veterans Affairs, the National Institute on Alcohol Abuse and the National Institute on Drug Abuse.

Mice lacking the so-called D2 receptor in their brains were generated at OHSU three years ago. The D2 receptor is one of five in the brain connected with a substance called dopamine, which is thought to regulate reward and some behaviors. Previous research suggests that alcohol and other drugs of abuse activate the brain's dopamine system. The release of dopamine in the brain creates a pleasurable sensation, prompting a craving for more alcohol. The importance of each dopamine receptor is being explored, but current data suggest that the D2 receptor may be one of the "sensors" that help power that craving.

"Our research shows that taking away the D2 receptor cut alcohol consumption in half," said Tamara Phillips, Ph.D., the lead author of the paper. Phillips is a research geneticist at the Portland VA Medical Center and professor of behavioral neuroscience at OHSU. "It also changed alcohol consumption to aversion, using a procedure where the animals had free choice over whether they drank alcohol or water."

The laboratory experiment involved placing mice in a cage with two bottles in it -- one filled with water, the other with ethanol. To make sure the mice were not simply avoiding the taste of alcohol, they were later given a choice between water and a saccharine (sweet) or quinine (bitter) solution. The location of the bottles was also switched, to assure that the mice were not going repeatedly to one bottle simply out of habit. The mice lacking the D2 receptor shied away from the alcohol, while the normal mice showed a preference for it. There were no differences between the normal mice and mice lacking D2 receptors in their consumption of saccharine or quinine. The mice missing the D2 gene did show a lower sensitivity to alcohol, meaning they demonstrated less disturbance in balance and activity at identical blood alcohol levels.

The D2 receptor has been the subject of intense scrutiny. Some researchers have proposed that mutations in the D2 receptor gene in humans are one of the roots of alcoholism. The OHSU and VA research paints a more complex picture. "It says that the D2 receptor is in some way involved in the animal's choice to drink or not to drink," said David Grandy, Ph.D., associate professor of physiology and pharmacology at OHSU and a co-author of the paper. "But how the receptor relates to euphoria or abuse of the drug isn't yet clear. It will require extensive genetic screening of humans to determine which specific mutations in the D2 receptor gene may be connected with alcoholism. Our research doesn't point towards a single 'alcoholic' gene, but rather towards a complex interaction between several receptors and systems in the brain."

Further research will focus on measuring those interactions. Phillips and other OHSU and VA scientists have also found that mice without a receptor sensitive to serotonin, another substance connected with pleasure, drink more than mice that have the gene. Phillips, Grandy and others are now working on breeding mice that lack both the D2 and serotonin receptors.

Related research is focusing on developing a strain of mice in which expression of the D2 receptor can be turned up or down, much like adjusting the volume control on a radio. In the drinking study, mice with half the D2 gene appeared to have normal drinking behavior, but their locomotor activity was altered. "There are probabaly many different combinations of effects between full function of this gene and a missing gene," said Malcolm Low, M.D., Ph.D., staff scientist at OHSU's Vollum Institute for Advanced Biomedical Research, associate professor of biochemistry and molecular biology and senior author on the article. Low is a neuroendocrinologist whose laboratory has produced many new strains of mice carrying specific gene mutations. Low's lab is now working on generating mice in which D2 expression can be regulated. "D2 is expressed in many parts of the brain. In some areas the receptor is important for locomotion, in others D2 receptors regulate the synthesis and release ! ! of dopamine itself. Continuing work will focus on isolating the location of the D2 receptors and zeroing in on the role they play in alcoholism," said Low.

While this research was done on mice, Phillips says it could have implications for treating alcoholism in humans. "Suppose you could create a drug that bound to the D2 receptor so that dopamine couldn't bind to that receptor at all. That would be like getting rid of the receptor. If you could do that, then you might be able to reduce drinking. However, the key will be battling the possible adverse side effects of such a drug, since dopamine is critically involved in many normal nervous system functions."