The National Institute on Alcohol Abuse and Alcoholism has recently published initial findings from an extensive multicenter project called the Collaborative Study on the Genetics of Alcoholism (COGA), centered at the State University of New York Downstate College of Medicine in Brooklyn. A sister study, also extensively examining the genetics of alcoholism, is under way at NIAAA headquarters in Rockville, Maryland.

In a linkage study of decreased brain wave activity in response to electrical stimulation (P3 event related potentials), COGA researchers found linkages on chromosomes 2 and 6 and possible linkages on chromosomes 5 and 13. P3 event related potentials are an interesting phenomenon. An event related potential is a positive brain wave that occurs following some type of sensory stimulation. A spike occurs three hundred milliseconds after a novel stimulus, and this is called a “P3” potential. For reasons that are not entirely clear, sons of male alcoholics demonstrate a lower amplitude of this type of brain wave. Since low P3 amplitude has been consistently associated with the risk for alcoholism, this study helps pinpoint sites for more detailed analysis.

An allele-sharing study of almost one thousand people from families affected by alcoholism found that the risk for alcoholism might involve traits controlled by genes on chromosomes 1, 2, and 7. Further evidence for the protective effect from the development of alcoholism on chromosome 4 was also presented. This protective effect involves the enzyme alcohol dehydrogenase and has been the focus of research in other settings. Alcohol dehydrogenase is an enzyme involved in the metabolism of alcohol. People with a certain form of this enzyme do not metabolize alcohol as efficiently as others, and will experience an unpleasant flushing reaction after ingesting alcohol.

COGA study data is presently being made available to researchers at other facilities, and its work continues as well.

A prospective study of the children in the original group is planned to see which children develop problems with alcohol.

Further study of their genetic characteristics will provide valuable information.

The NIAAA study confirmed the finding of the protective effect on chromosome 4 related to the alcohol dehydrogenase gene. Previous family studies had suggested that this effect was limited to Asians who experience an unpleasant fiushing sensation when drinking alcohol. But these and other studies suggest that a more subtle effect may be present in other racial groups. The exact mechanism of the protective effect is still under study.

Another finding of the NIAAA study identified a linkage with a specific portion of chromosome 11 in people genetically at risk for alcoholism. Chromosome 11 has been identified as containing genes that control the synthesis of neurotransmitters important in addiction, such as serotonin and dopamine. This is an example of how a linkage study, combined with previous research findings, points the way towards further study.

Two recent studies with knock-out animals have increased our understanding of the actions of cocaine. Researchers at NIDA bred knock-out mice which lacked a specific receptor for the neurotransmitter serotonin - 5HT(1b). These mice, when compared to their unaffected cousins, were more sensitive to the effects of cocaine and more strongly attracted to the drug. 5HT(1b) knock-out mice also react more strongly to alcohol and are more impulsive. Their response to different experimental situations with different drugs should prove helpful in our understanding of the molecular mechanisms behind addiction.

The second study, also coming out of NIDA, found an unexpected connection between a sensitization response to cocaine and the lack of a gene that controls the biological clock. This study used knock-out strains of fruit flies, which have some genetic similarity to humans. The gene knocked out in the fruit flies was the one regulating the biological clock, a timing device that controls various bodily processes occurring cyclically over time. Sensitization to a drug like cocaine is manifested by an increased response to its effects after repeated exposures. This was blunted in the fruit flies that lacked the clock gene. The implication of this finding is not yet clear, but it opens up a new area of potential inquiry that should prove helpful in furthering our understanding of how the brain responds to cocaine and other drugs.

Knock-out mice were used in a recent study of nicotine addiction. In this study, mice were bred so as to lack a component of the nicotinic acetylcholine receptor in the brain, a receptor for the neurotransmitter acetylcholine which also binds nicotine. These knock-out mice did not self-administer nicotine, unlike their unaffected cohorts. Since self-administration is a component of drug addiction, it was concluded that this receptor subunit must be involved in the addictive properties of nicotine. Another study found that people who inherit the less-active variant of a common liver enzyme, CYP2A6, which metabolizes nicotine and other drugs, were less likely to develop addiction to nicotine. This might help explain why some people become addicted to nicotine more easily than others.

Elizabeth Connell Henderson, M.D.

Glossary

Appendix A: Regulation of Addictive Substances

Appendix B: Sources of Additional Information