Abusive inheritance; gene implicated in alcoholism may influence a wide array of drug abuse.

Gene implicated in alcoholism may influence a wide array of drug abuse

Of the approximately 100,000 genes that make up humanity's chemical blueprint, the D2 dopamine receptor gene currently attracts by far the most controversy. For more than two years, scientists have wrangled over whether a particular form of the D2 gene confers a susceptibility to severe alcoholism.

The latest twist in this debate goes beyond the bottle. A research team directed by neuroscientist George R. Uhl of Johns Hopkins University School of Medicine in Baltimore now reports that a second version of the D2 dopamine receptor gene - called B1 - appears more often among people who indulge heavily in several addictive drugs, including alcohol, cigarettes, marijuana, cocaine, heroin, tranquilizers, and amphetamines.

Many such drug abusers consume several types of substances, and few abstain from alcohol, Uhl's group notes.

This second form of the D2 gene shows a moderate, statistically significant association with heavy use of several drugs, the scientists report in the September ARCHIVES OF GENERAL PSYCHIATRY. Still, the absence of a robust link leaves considerable room for social and psychological influences on alcoholism, cigarette dependence, and other drug abuse, they hold (SN: 2/1/92, p.69). It also suggests that additional genes help create a proclivity for substance abuse, the investigators note.

Proponents of the D2 dopamine receptor gene as a prominent player in severe alcoholism welcome its implication in a broader spectrum of drug abuse, while critics see significant flaws in the new study. Both camps anxiously await the findings of federal researchers currently employing advanced molecular scanning techniques to search for specific chemical changes in the D2 gene that may distinguish alcoholics from non-alcoholics.

Uhl and his associates collected blood samples from 232 drug users who met the criteria for moderate or heavy use of several drugs - usually including alcohol and cigarettes - and from 56 controls who either used no drugs or on rare occasions consumed alcohol, cigarettes, or marijuana. The researchers isolated DNA from each blood sample, used special enzymes to cut the DNA into fragments, and placed the pieces into an electrically charged gel that sorted them into identifiable patterns. The investigators then used chemical probes to mark specific amino acid variations along two stretches of the D2 gene.

Heavy users of several drugs displayed a substantial excess of the B1 form of the D2 gene - which features a chemical modification near an "active" region responsible for producing and regulating proteins of dopamine receptors on brain cells. Dopamine serves as a chemical messenger and has important effects on pleasure-seeking behaviors.

One-third of the multiple-drug users displayed the B1 variant, compared with 14 percent of the controls, Uhl's group asserts. Further analysis indicates that alcoholics did not skew these results: One-third of the drug users who were not heavy alcohol drinkers possessed the B1 variant.

However, the extent of the association between the B1 variant and the abuse of multiple substances falls far short of that reported between the D2 gene and alcoholism by Kenneth Blum, a psychopharmacologist at the University of Texas Health Science Center at San Antonio, and Ernest P. Noble, a psychiatrist at the University of California, Los Angeles (SN: 9/21/91, p.190).

Noble views the new data on multiple-drug abuse as supportive of his theory that the dopamine receptor gene is one of several genes that predispose people to a broad spectrum of substance use and abuse. As further evidence for this notion, Noble cites an unpublished study conducted with Blum of two D2 gene variations - the same ones studied by Uhl's group - which showed an excess of both forms among cocaine abusers who abstain from other drugs.

A gene with close connections to the dopamine system probably orchestrates sensations of reward and drug dependence, Noble argues. He suspects that a particular form of the D2 dopamine receptor gene serves as a "gateway gene" that predisposes people to giving all sorts of drugs an initial try.

Researchers who previously challenged any connection between the D2 dopamine receptor gene and alcoholism also doubt the drug-use data presented by Uhl's group. Drug users in Uhl's sample, which consisted entirely of white adults, were not broken down into separate ethnic groups for genetic analysis, notes psychiatrist Joel Gelernter of the Department of Veterans Affairs Medical Center in West Haven, Conn. Several recent studies that take into account the ethnic backgrounds of participants show no link between the D2 gene and alcoholism, he says.

In fact, six studies reported in the past two years - including one directed by Gelernter (SN: 6/1/91, p.351) - fail to reveal any D2 gene link with alcoholism, whereas only the two studies conducted by Noble and Blum show a large excess of the D2 gene variant among alcoholics, Gelernter contends.

"There is no proposed mechanism to explain how a D2 dopamine receptor gene affects alcohol or drug use," Gelernter argues. Moreover, a molecular analysis of 36 variants of the D2 dopamine receptor gene, including those studied by Uhl's group, uncovered no chemical differences thought to alter protein production, he maintains.

"If a connection exists between this gene and drug abuse, it needs to be demonstrated by finding specific mutations that occur more often among abusers," Gelernter contends.

Such a study is under way at the National Institute of Mental Health (NIMH) in Bethesda, Md. Researchers take individual DNA samples, amplify the D2 dopamine receptor gene, make copies of it, and pinpoint chemical mutations using a recently developed molecular scanning procedure.

The project now includes more than 100 DNA samples from alcoholics and healthy controls. Gelernter, Blum, and Noble have contributed DNA from their own experiments to the NIMH study.

A preliminary analysis failed to identify any mutations that distinguish the D2 dopamine receptor genes of alcoholics from those of controls, says NIMH psychiatrist Pablo Gejman, who heads the study. Mutations refer to random changes in specific chemical building blocks along a gene. Studies such as Uhl's target mutations along a small portion of the D2 dopamine receptor gene, whereas the NIMH researchers can identify chemical changes along the entire gene.

"This is a very hot topic," Gejman says. "My personal feeling is that it's improbable we'll find an important D2 gene mutation in alcoholics. The genetic locus for a predisposition to alcoholism may lie elsewhere."

Wherever that predisposition site lies, the genetics of alcoholism continues to tantalize researchers. In the Oct. 14 JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, a research team led by psychiatrist Kenneth S. Kendler of the Medical College of Virginia in Richmond asserts that genes account for about half of a woman's tendency toward alcoholism, a figure comparable to that previously reported for men.

The researchers base their conclusion on a study of 1,030 pairs of identical and fraternal twins, each pair consisting of two women. Alcoholism occurred far more often among both identical twins than among both fraternal twins, the researchers report.

Kendler says he suspects the D2 dopamine receptor gene may indeed play a role in male alcoholism, although the way in which it contributes to uncontrolled alcohol consumption remains a matter of speculation. Alcoholism-related genes among women remain even more mysterious, he notes.