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NIDA Supported Research Volume 12, Number 4 July/August 1997

Promising Advances Toward Understanding the Genetic Roots of Addiction

By June R. Wyman, NIDA NOTES Staff Writer

At a major scientific meeting, a scientist announced to a spellbound audience that he had identified some of the genes associated with drug abuse. He described the mutations in those genes that lead people to abuse marijuana, heroin, cocaine, and other drugs. His landmark discovery brought scientists a giant step closer to dramatically curbing drug abuse. Although some drug abuse researchers are predicting this tale could come true as early as the next 5 to 10 years, for now it is fiction.

Currently, scientists agree that genetics is involved in drug abuse, but the consensus ends there. Many genes are thought to act together to make someone more likely to abuse drugs. But exactly which genes those are and what they do are the subject of a lively scientific debate. Further, since drug addiction appears to be the product of both heredity and environment, the roles of the two are hard to separate.

At NIDA, a Genetics Workgroup is trying to sort out these issues. The group's mission is to assess the state of the science, identify research gaps, and decide what studies are needed to untangle the genetic roots of addiction. Its members consult with experts from around the country to get advice on what directions NIDA should take, according to Dr. Jonathan Pollock of NIDA's Division of Basic Research, who chairs the group.

Meanwhile, amid the debate, new scientific information is emerging, giving scientists leads that may generate new strategies for drug abuse prevention and treatment.

Family Resemblances

Whether or not someone feels good after smoking marijuana is strongly influenced by heredity, report NIDA-funded grantees from Harvard Medical School. Their conclusion comes from a study of 352 pairs of identical male twins and 255 pairs of fraternal male twins, all of whom had smoked marijuana more than five times in their lives. Identical twins have exactly the same genes, while in fraternal twins about half the genes are identical.

Dr. Ming Tsuang, Dr. Michael Lyons, and their colleagues compared the identical twins' answers with the fraternal twins' answers to a set of questions about how good or bad they felt after smoking marijuana. The identical twins' answers were significantly more alike than those of the fraternal twins. The researchers interpret their data to mean that genetic factors have a significant impact on whether someone will enjoy marijuana.

It is this kind of research that begins the search for drug abuse genes. Although studies of twins and families cannot pinpoint specific genes related to drug addiction, they can look closely at people who share a drug abuse disorder and a common genetic makeup. "Twin studies are promising because they ask exactly what is heritable," says Dr. Harold Gordon of NIDA's Division of Clinical and Services Research. Then, using blood samples, molecular biologists can examine these individuals' genetic material, or DNA, to locate shared genetic characteristics, he says.

To advance such work, NIDA has expanded funding to epidemiologists who work with large numbers of twins or families but have not previously studied addiction to drugs other than nicotine and alcohol. For example, Dr. Kenneth Kendler of Virginia Commonwealth University in Richmond has been studying the genetic basis of nicotine dependence in a large database of twins and siblings in Virginia. NIDA's support has allowed him to launch an epidemiologic survey of those twins that will flag vulnerability to a wide range of drugs including nicotine, cocaine, barbiturates, opiates, inhalants, and marijuana. To measure gender differences, he is doing separate analyses of female/female twins and male/male twins.

Dr. Roy Pickens of NIDA's Division of Intramural Research (DIR) in Baltimore, with colleagues at Johns Hopkins University in Baltimore and the University of Minnesota in Minneapolis, also has been studying twins. Their study looked at same-sex twins, half identical and half fraternal, with coexisting, or comorbid, drug addiction, alcohol abuse, and/or mental health problems. The researchers' analyses suggest that common genetic factors are involved in drug and alcohol abuse and certain psychological disorders in men. They speculate that this may account for some of the comorbidity among these disorders. Genetic influences were not identified in women, probably because there were not enough women in the study, says Dr. Pickens.

Likely Candidate Genes

Meanwhile, geneticists are homing in on particular drug abuse genes - a daunting task, given that humans have around 100,000 genes and, of those, more than 40,000 may be expressed in the brain, where drugs of abuse act. Still, many scientists are optimistic. "We've known for a long time that genetics is an important part of an individual's response to drugs of abuse," says Dr. John Crabbe, a NIDA grantee at Oregon Health Sciences University in Portland. "What we're able to do now is get our hands on specific candidate genes."

Of particular interest are genes that control the brain chemical dopamine, which is associated with movement and pleasure, including pleasure from drug use. "Genes in the dopamine circuit are likely candidates, and most of these have been examined at least to some degree," says Dr. George Uhl, chief of DIR's Molecular Neurobiology Branch. This work is being done in mice, which have critical genetic similarities to humans. Also, scientists know more about the genetic makeup of mice than that of any other mammal except humans.

One approach to studying the genes that may influence drug responses is to remove, or "knock out," a candidate gene in mice and see what happens. For example, DIR Scientific Director Dr. Barry Hoffer and scientists from two Swedish laboratories recently used genetic engineering techniques to knock out the gene for a protein called Nurr1. The brains of these mice lacked the two major groups of dopamine neurons and, thus, could not produce any dopamine.

The scientists conclude that in mice Nurr1 is critical for normal development of dopamine-containing nerve cells, and they speculate that development of those cells may be abnormal in people who are vulnerable to substance abuse. "These people may be abusing drugs in an attempt to counteract the deficiency," says Dr. Hoffer, who did the study with scientists from the Karolinska Institute and the Ludwig Institute for Cancer Research, both in Stockholm.

"Medications could be developed that interact with Nurr1 and thus regulate dopamine levels in the brain," Dr. Hoffer speculates. "These medications could be useful in treating an underlying disorder that might make some people more likely to abuse drugs."

Another approach to studying the genetics of addiction is to study responses to drugs in genetically identical strains of mice. At Oregon Health Sciences University and the Portland Veteran's Administration Medical Center, Dr. Crabbe and Dr. John K. Belknap have studied more than 25 strains of these inbred mice. "There are big differences among strains in whether they self-administer different drugs," Dr. Crabbe observes. For example, a strain called DBA/2 refuses most drugs of abuse, while C57BL/6 mice seem to like almost everything, including alcohol, morphine, cocaine, phenobarbital, and diazepam. Other inbred strains fall between these extremes. "This work shows that specific genes cause animals to like particular drugs, so that vulnerability to drug abuse is partly under genetic control," says NIDA's Dr. Pollock.

So the evidence from animal studies is compelling. But finding equally strong evidence in humans for a genetic influence on drug addiction has proved trickier. Although a number of genes have been implicated, none has been clearly linked to drug addiction.

At DIR, Dr. David Vandenbergh, Dr. Uhl, and their coinvestigators are looking for genes that may be involved in drug abuse by comparing DNA from drug abusers to that of people who do not abuse drugs. So far the strongest candidate is a variant of a gene that tells the body to produce an enzyme called COMT (catechol-o- methyltransferase). Widespread throughout the body, this enzyme helps break down and inactivate dopamine and related substances. COMT occurs in two genetically determined forms: low activity and high activity. "We found that the high-activity forms of the gene and the enzyme are found more often in drug abusers," Dr. Vandenbergh says. If further work confirms this finding, then drugs that lower COMT activity could be tested as treatments for drug addiction, he says.

Gene Hunters

What will it take to locate the particular genes involved in human drug addiction? Some scientists think that the best bet is what scientists call a genome-wide scan. This method, which was recently used to identify the genetic defect for Parkinson's disease, entails several steps:

• find families with high rates of the disorder;

• analyze blood samples from these people to locate the genetic markers, or stretches of DNA, that family members with the disorder seem to share that are different from those who do not have the disorder;

• scan all known human genes using sources such as the National Institutes of Health's Human Genome Project, and try to find some connection - for example, a gene on the chromosome that is known to regulate dopamine levels; and

• go back to the blood samples to look for shared mutations in those genes.

But applying this method to drug addiction will not be straightforward. "What should we look at? Drug abuse per se? Sensation seeking? Specific biological markers? We really don't know," says Dr. Gordon.

"These genes could operate in many ways. They might make you seek sensations or make it hard to withdraw once you start abusing drugs or make you get higher than other people. Or maybe you need all of these to become a drug abuser," says Dr. Pickens.

Dr. Crabbe in Portland is one of those researchers who thinks that identifying some of the genes involved in drug abuse and addiction is in sight. "That's the big thing that will happen in this field in the next 5 to 10 years. We'll turn the theory that genes influence addiction into the identification of specific genes," he predicts.

Sources

Crabbe, J.C.; Belknap, J.K.; and Buck, K.J. Genetic animal models of alcohol and drug abuse. Science 264:1715-1723, 1994.

Gordon, H.W. Human neuroscience at National Institute on Drug Abuse: implications for genetics research. American Journal of Medical Genetics 54:300-303, 1994.

Lyons, M.J.; Toomey, R.; Meyer, J.M.; Green, A.I.; Eisen, S.A.; Goldberg, J.; True, W.R.; and Tsuang, M.T. How do genes influence marijuana use? The role of subjective effects. Addiction 92(4):409-417, 1997.

Pickens, R.W.; Svikis, D.S.; McGue, M.; and LaBuda, M.C. Common genetic mechanisms in alcohol, drug, and mental disorder comorbidity. Drug and Alcohol Dependence 39:129-138, 1995.

Uhl, G.R.; Gold, L.H.; and Risch, N. Genetic analyses of complex behavioral disorders. Proceedings of the National Academy of Sciences 94:2785-2786, 1997.

Vandenbergh, D.; Rodriguez, L.R.; Miller, I.T.; Uhl, G.R.; and Lachman, H.M. High-activity catechol-o-methyltransferase allele is more prevalent in polysubstance abusers. American Journal of Medical Genetics 74:439-442, 1997.

Zetterstrom, R.H.; Solomin, L.; Jansson, L.; Hoffer, B.J.; Olson, L.; and Perlmann, T. Dopamine neuron agenesis in Nurr1-deficient mice. Science 276:248-250, 1997.

From NIDA NOTES, July/August 1997

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