articles

Reward Deficiency Syndrome

Kenneth Blum, John G. Cull, Eric R. Braverman
and David E. Comings

cont.

Reward Cascade

Alcoholism and Genes

An alteration in any of the genes that are involved in the expression of the molecules in the reward cascade might predispose an individual to alcoholism. Indeed, the evidence for a genetic basis to alcoholism has accumulated steadily over the past five decades. The earliest report comes from studies of laboratory mice by the American psychologist L. Mirone in 1952. Mirone found that, given a choice, certain mice preferred alcohol to water. Gerald McLearn at the University of California at Berkeley took this a step farther by producing an inbred mouse (the C57 strain) that had a marked preference for alcohol. The alcohol-preferring C57 strain bred true through successive generations-it was the first clear indication that alcoholism has a genetic basis (McLearn and Rodgers 1959).

The first evidence that alcoholism has a genetic basis in human beings came in 1972 when scientists at the Washington University School of Medicine in St. Louis found that adopted children whose biological parents were alcoholics were more likely to have a drinking problem than those born to nonalcoholic parents (Schuckit, Goodwin and Winokur 1972). In 1973 Goodwin and Winokur, working at the Psykologisk Institut in Copenhagen, studied 5,483 men in Denmark who had been adopted in early childhood. They found that the sons born to alcoholic fathers were three times more likely to become alcoholic than the sons of nonalcoholic fathers.

In the late 1980s research on the inheritance of alcoholism suggested that there might be important genetic differences between alcoholics and nonalcoholics (Cloninger, Bohman and Sigvardsson 1981; Goodwin 1979). One of us (Blum) and his colleagues suspected that the activity of the chemical signaling molecules in the reward pathways of the brain might be involved. Over the course of two years we compared eight genetic markers associated with various neurotransmitters (including serotonin, endogenous opioids, GABA, transferrin, acetylcholine, alcohol dehydrogenase and aldehyde dehydrogenase). In each instance we failed to find a direct association between the genetic markers and alcoholism.

The opportunity to investigate a ninth genetic marker arose after Olivier Civelli of the Vollum Institute at Oregon University cloned and sequenced the gene for one form of the dopamine D2 receptor. The D2 receptor is one of at least five physiologically distinct dopamine receptors (D1, D2, D3, D4 and D5) found on the synaptic membranes of neurons in the brain (Sibley and Monsma 1992). Previous studies had established that D2 receptors are expressed in neurons within the cerebral cortex and the limbic system, including the nucleus accumbens, the amygdala and the hippocampus. Because these are the same areas of the brain (with the exception of the cortex) that are believed to be involved in the reward cascade, Civelli's work provided the opportunity to investigate an important molecular candidate for genetic aberrations among alcoholics.

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Chromosome 11

The technique we used to distinguish between the D2 receptor genes of alcoholics and those of nonalcoholics relies on the detection of restriction-fragment-length polymorphisms (RFLPs). This approach involves the use of DNA-cutting enzymes (restriction endonucleases) that cleave the DNA molecule at specific nucleotide sequences. If there are genetic differences between two individuals such that a restriction enzyme cuts their DNA along different points in (or near) a gene, the resulting fragments of their genes will be of different lengths. These differing fragments, or polymorphisms, are recognized by the use of a radioactively labeled DNA probe-in this case a short sequence of the D2 receptor gene-that binds to a complementary DNA sequence on the fragments. Radiolabeled fragments of different lengths signify a difference in the cleavage sequence recognized by the restriction enzyme (Grandy et al. 1989).

RFLP Method

The restriction enzyme (Taq 1) cuts the nucleotide sequence at a site just outside the coding region for the D2 receptor gene. This produces the Taq 1A polymorphisms. To date there are four Taq 1A alleles known, the A1, A2, A3 and A4 alleles. The A3 and A4 alleles are rare, whereas the A2 allele is found in nearly 75 percent of the general population and the A1 allele in about 25 percent of the population.

In 1990 we used the Taq I enzyme to search for Taq IA polymorphisms in the DNA extracted from the brains of deceased alcoholics and a control population of nonalcoholics. The results were striking: In our sample of 35 alcoholics we found that 69 percent had the A1 allele and 31 percent had the A2 allele. In 35 nonalcoholics we found that 20 percent had the A1 allele and 80 percent had the A2 allele.

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