Do chronic alcoholics "have only themselves to blame" for theiraddiction to ethanol? Or are societal pressures the cause of theirpathological over-indulgence? What share of alcoholism, if any, canbe laid at the door of genetic inheritance?
Certainly, dependence on drink runs in families, but is there actuallya gene for alcoholism? Yes, at least one gene, on human chromosome11, according to recent research reported by molecular geneticists.The latest such finding, in the April issue of Nature Medicine,suggests not just cause, but cure _ or at least, treatment _ for theself-destructive addiction.
Its title: "Bromocriptine in the treatment of alcoholics with the D2dopamine receptor A1 allele."
Bromocriptine is a powerful drug prescribed mainly for Parkinson'sdisease, (but also for some problems of lactation). It acts as anagonist to the D2 receptor of the neurotransmitter dopamine, which iscurrently suspected of complicity in addiction to drugs of abuse.
"Previous research," writes the paper's principal author, biochemistand psychiatrist Ernest Noble, "has identified certain areas of thebrain that are involved in reinforcement of reward behavior. Forexample, if the nucleus accumbens is stimulated, the animal feelspleasure, feels reward.
"When drugs are given to animals, Noble continued, "or for thatmatter to humans, we find that in those areas of reward, levels of theneurotransmitter, dopamine are increased. The dopamine thenstimulates its receptors, which results in the feeling of satisfaction,reward or pleasure."
Such gratifying sensations reward ethanol ingestion, and prompts"another round of the same."
Noble, the paper's principal author, chairs alcohol studies at theUniversity of California, Los Angeles (UCLA), and directs UCLA'salcohol research center. In the 1970s, he headed the National Instituteof Alcohol Abuse and Alcoholism.
"In 1990," he told BioWorld Today, "my colleagues and I looked forgenes that might be associated with alcoholism. Obviously the D2dopamine receptor gene stood high on our list, because of itsinvolvement in pleasure or reward. What we found, as did others,were two alleles on that gene, A1 and A2. "Severe alcoholics, wedetermined, had significantly higher prevalence of the A1 allele thandid non-alcoholics."
Since then, he and his co-authors have extended this A1 allelicindictment of that gene to cocaine, nicotine and the food addiction ofobesity.
A1 is a "minor allele," Noble said, which occurs in only 20 percent ofthe general population, of which an estimated 7 percent arealcoholics. Of that affected group, fully half have the A1 form of thegene.
"What this implies," he hypothesizes, "is that A1 people are bornwith a deficiency of their reward system. And in order to overcomethat, to feel good in life, they may take alcohol, which by releasingdopamine stimulates the dopamine receptor.
"The only catch with that," Noble pointed out, "is that dependencybegins to develop with alcohol, people become alcoholics, or cocaineaddicts, or cigarette smokers, or compulsive food eaters."
UCLA's brain bank supplied the final link: people who had the AIand A2 alleles" Those with A1," Noble said, "had a significantlylower number of D2 dopamine receptors _ 30 percent or better _than those who don't have the allele."
With this research background, he and his colleagues then asked thepractical question: "What would happen if we gave alcoholics a D2dopamine agonist, that is, a stimulator of the D2 dopaminereceptors?"
One primary drug candidate they looked at was bromocriptine, whichcrimps the activity of dopamine acting on the brain's reward centers.To test its effects in short-circuiting the pleasure centers in the brainsof alcoholics, he set up a trial in conjunction with Bruce Lawford ofthe Royal Brisbane Hospital, in Queensland, Australia.
"That hospital," Noble observed, "treats a lot of alcoholics, and thenice thing about it is that those alcoholics, in contrast to America, arenot allowed to leave the hospital, so not allowed to drink. So wecould really do a good trial there."
He set up a protocol for the Australian collaborators; they ran thetests, administered the bromocriptine, and sent the blood samples toUCLA for molecular-genetics and statistical analysis.
Three measurable hallmarks characterize alcohol addiction, andframed their study: One is an uncontrollable craving for alcohol. Twois extreme anxiety. Three is deep, pervasive depression.
The six-week, double-blind, placebo-controlled trial that Noblereports in Nature Medicine initially enrolled 83 volunteers, 78 menand five women, average age, 44, hospitalized in Brisbane forchronic alcoholism. By the end of the experiment, 31 of the subjectshad "left the hospital against medical advice." Only a small sample of52 remained to evaluate the effect of bromocriptine on allelic linkageof A1 and A2 to craving, anxiety and depression.
Short-Circuiting Craving, Anxiety, Depression
One over-all bottom-line result: Craving decreased by 34 percent inthe drug-treated group, vs. 8.5 percent among those who receivedlook-alike vitamin-C placebo tablets. Moreover, craving dropped 68percent in the subgroup of subjects carrying the A1 allele in theirgenome, compared with only 10.2 percent of those with A2inheritance.
Anxiety scores followed the same pattern, declining more among thebromocriptine than placebo cohorts, and much more in A1 than A2individuals.
"For depression, that feeling of doom and gloom," Noble said, "wedon't necessarily give alcoholics antidepressants, because thedepression resolves on its own." In the test, depression also wentdown, but with no difference between the A1 subgroup onbromocriptine and the other groups.
The group that did best, in which craving and anxiety came downsignificantly, were those alcoholics with the A1 allele who got thedrug. "Moreover," Noble added, "those individuals also did the bestin terms of they stayed longer in the hospital, and were moreamenable to treatment."
Ergo, he pointed out, "using molecular genetics, we can now separatealcoholics into two groups. He proposes this scenario:
"An alcoholic comes into a treatment center, a blood specimen istaken, and through a PCR reaction, we can identify those who've gotthe A1 allele. Then we can provide those people with apharmacological treatment, such as bromocriptine. Those who've gotthe A2 allele, I think, can be taken care of better by psychosocialintervention."
Noble makes clear that "This is a preliminary study; the firstbehavioral study ever to use a molecular-genetics approach to dissectout the different types of alcoholics, and then test a treatment." Buthe also emphasizes that it has equal potential for the other dopaminereceptor addictions, cocaine, nicotine and obesity.
His next goal is to repeat the experiment on a larger, longer-termscale, perhaps at the UCLA-affiliated Veterans' Hospital Center, "assoon as we can get the money.
"I think we would like to do a much larger sample of individuals inthe U.S.," Noble concluded. "Have a larger proportion of womenincluded. And also see if effects of bromocriptine are sustained overlonger periods of time, especially when these alcoholics are releasedto the community, and are exposed again to the vicissitudes andtemptations of drink." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.