A genetic difference at the opiate receptor gene affects a person’s response to alcohol

• Previous research has implicated the brain’s opioid system in the development of alcohol-use disorders.
• New findings indicate that individuals with the G variant of the A118 polymorphism of the OPRM1 gene have greater subjective feelings to alcohol’s effects as well as a greater likelihood of a family history of alcohol-use disorders.

Previous research has implicated the brain’s opioid system in the development of alcohol-use disorders. The mu-opioid receptor, which is encoded by the OPRM1 gene, is the primary site of action for opiates with high abuse potential, such as opium and heroin, and may also contribute to the effects of non-opioid drugs, such as cocaine and alcohol. Findings published in the December issue of Alcoholism: Clinical & Experimental Research indicate that individuals with the G variant of the A118 polymorphism of the OPRM1 gene have greater subjective feelings to alcohol’s effects as well as a greater likelihood of a family history of alcohol-use disorders.

“Alcohol releases endogenous opiates which, in turn, seem to influence the mesolimbic dopamine system,” said Kent E. Hutchison, associate professor of psychology at the University of Colorado at Boulder and lead author of the study. “This system is involved in craving and the motivation to use alcohol and drugs. Thus, it is alcohol’s effects on endogenous opioids that act as the gateway through which alcohol may influence this system.”

“It is well known that alcohol dependence tends to run in families,” said Robert Swift, professor of psychiatry and human behavior at Brown University and Associate Chief of Staff for Research at the Providence VA Medical Center. “The inheritance of alcoholism is complex, but there are suggestions that the opiate systems in the brain are involved. Our brains contain proteins, called enkephalins and endorphins, that act like morphine and other opiates derived from the poppy plant. Several researchers have shown that persons with a family history of alcoholism tend to have differences in blood levels of beta-endorphin, a natural opiate hormone, compared to persons without a family history of alcoholism. Children of alcoholics, who are not themselves alcoholics, have lower levels of beta-endorphin than do children of non-alcoholics. Also, when young adults with a family history of alcoholism drink alcohol, they increase their blood levels of beta-endorphin more than those without a family history of alcoholism.”

A special protein called the mu-opioid receptor, which is located in the membranes of nerve cells, detects internal opiate neurotransmitters, such as beta-endorphin, that the brain uses to allow nerve cells to communicate with each other. Previous research has shown that the G variant of this gene has a slightly different receptor protein, which causes a big difference in how well the receptor connects with beta-endorphin. For example, the G variant receptor binds three times more tightly than the A variant to beta-endorphin, which means that a nerve cell with the G variant is more greatly affected by beta-endorphin. The net result is that dopamine cells, which play a role in motivation and reinforcement, become more stimulated.

For this study, participants comprised 38 students (20 male, 18 female) at the University of Colorado, 21 to 29 years of age, who indicated drinking patterns classified as moderate to heavy. Participants were either homozygous for the A allele (n=23) or heterozygous (n=15). Each received intravenous doses of alcohol that were designed to cause breath alcohol concentration (BAC) levels of .02, .04, and .06. Researchers measured subjective intoxication, stimulation, sedation, and mood states at baseline and at each of the three BAC levels.

Results indicate that individuals with the G allele had higher subjective feelings of intoxication, stimulation, sedation, and happiness across trials as compared to participants with the A allele.

“The implication is that the trajectory of alcohol dependence may be different among individuals with the G allele,” said Hutchison. “If these individuals have a different level of sensitivity, they may also have a differential level of risk for developing alcohol dependence. They may also respond to alcohol treatments differently, especially those that target the mu-opioid receptors, such as naltrexone.” Naltrexone treatment is designed to reduce feelings of euphoria after alcohol consumption by blocking beta-endorphin; in fact, a recent study by Dr. David Oslin and colleagues at the University of Pennsylvania suggests that individuals with the G allele may respond better to naltrexone treatment.

The study also found that participants with the G allele were almost three times more likely than those with the A allele to report a family history positive for alcohol-use disorders.

“This manuscript provides further evidence that how one responds to alcohol is inherited,” said Swift. “However, it should be noted that the increased risk for alcoholism does not mean that someone with the G allele will necessarily become an alcoholic. The development of alcoholism is only partially determined by heredity. Environmental factors and life experience are as important as heredity.”

“These findings add to our expanding knowledge about how genetic factors may influence responses to alcohol and the risk for developing alcohol dependence,” said Hutchison. “Given recent growth in our knowledge about the human genome, we will see many more of these kinds of studies in the future.” He and his colleagues plan to continue examining the influence of the G variant of the A118 polymorphism of the OPRM1 gene, as well as other genetic variants, on response to alcohol as well as tobacco and marijuana.

“The inheritance of alcoholism is complex,” said Swift, “and there are certainly more genes, still undiscovered, that are involved in alcoholism. The search for these genes is an active area of investigation and well worth pursuing. Understanding the genetic basis of the response to alcohol and how it may predict risk for the development of alcoholism could be used as a kind of genetic counseling to help individuals at risk. Persons carrying a risk gene, if they are made aware of it, may be able to alter their drinking and reduce their risk of developing alcoholism.”