Study advances evidence for receptor’s role in alcohol pleasure and problems

A genetic variant of a receptor in the brain’s reward circuitry heightens the stimulating effects of early exposures to alcohol and increases alcohol consumption, according to a new study by researchers at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health (NIH).

Conducted in rhesus monkeys, the study extends previous research that suggests an important role for a similar brain receptor variant in the development of human alcohol use disorders. A report of the findings is published in the March, 2007 issue of the Archives of General Psychiatry.

“Although the pathway to alcoholism is influenced by many factors, our findings affirm that individuals who possess this receptor variant may experience enhanced pleasurable effects from alcohol that could increase their risk for developing alcohol abuse and dependence,” notes Markus Heilig, M.D., Ph.D., NIAAA Clinical Director and the study’s senior author.

Molecules known as opioid peptides bind to opioid receptors in the brain to signal experiences of reward and reinforcement, as well as the euphoria and other positive subjective effects produced by alcohol. Previous studies have shown that, among the brain’s various subtypes of opioid receptors, the mu-subtype is most likely responsible for transmitting alcohol’s positive effects.

“We also know that there are several genetic variants of the human mu-opioid receptor,” notes first author Christina Barr, V.M.D., Ph.D., a lead investigator in NIAAA’s Laboratory of Clinical and Translational Studies and Laboratory of Neurogenetics. “One of these, designated 118G, has a greatly enhanced ability to bind opioid peptides. People who have this variant of the receptor have reported increased euphoria following alcohol consumption.”

Drs. Barr, Heilig, and their colleagues note that recent studies have linked the 118G mu-opioid receptor with alcohol dependence in humans. In the current study, the researchers explored the link between genetic variants of mu-opioid receptors and alcohol-related behaviors in a group of 82 rhesus monkeys.

“A mu-opioid receptor variant that is functionally similar to the human 118G variant occurs in these animals,” explained Dr. Barr. “That is, it also has a greatly enhanced ability to bind opioid peptides. We hypothesized that monkeys that had the gene for this receptor variant would experience enhanced alcohol stimulation and, therefore, consumption.

Groups of monkeys had access to both alcoholic and non-alcoholic solutions for one hour per day for a period of six weeks. Researchers measured the animals’ alcohol intake and post-intake activity, and determined which monkeys carried the gene for the mu-opioid receptor similar to the human 118G receptor. Activity measures are commonly used in animal studies to assess alcohol’s pleasurable effects. As predicted, the researchers found that monkeys with the variant gene showed increased activity following alcohol consumption. They also found that male animals with the variant had a clear preference for the alcohol solution and consumed on average almost twice as much alcohol as other animals. Males with the variant also became intoxicated on almost 30 percent of testing days, while other animals did so only on an average of 8 percent of testing days.

“The male-restricted effect of this gene is interesting, and parallels other recent evidence that opioid transmission may play a greater role in alcohol problems among some males than among females,” explained Dr. Heilig. This information also complements recent data suggesting that alcohol-dependent people with the gene for the 118G receptor have a better therapeutic response to medications that block opioid receptors. More broadly, the finding underscores the important role that the pleasurable and stimulating initial effects of alcohol play in the subsequent development of alcohol problems.”

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.

The National Institutes of Health (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. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.