articles
Reward Deficiency Syndrome
Kenneth Blum, John G. Cull, Eric R.
Braverman
and David E. Comings
cont.
Behavioral anomalies such as conduct disorder (in which children violate
social norms and the rights of others) and antisocial personality (the adult
equivalent of conduct disorder) are often found to be associated with alcohol
and drug problems. Several investigators have noted that sociopathic behavior
in children predicts a tendency toward antisocial personality behavior,
alcohol abuse and drug problems later in life. An analysis of 40 studies
showed a strong positive correlation between alcoholism and drug abuse,
between alcoholism and antisocial personality, and between drug abuse and
antisocial personality (Schubert et al. 1988).
Although there is little known about the genetics of cocaine dependence,
extensive scientific data are available on the effects of cocaine on brain
chemistry. The current view is that the system that uses dopamine in the brain
plays an important role in the pleasurable effects of cocaine. In animals, for
example, the principal location where cocaine takes effect is the dopamine D2
receptor gene on chromosome 11 (Koob and Bloom 1988). Recently George Koob and
his colleagues of the Scripps Research Institute in La Jolla, California,
found evidence suggesting that the dopamine D3 receptor gene is a primary site
of cocaine effects. The exact effect of cocaine on gene expression is unknown.
However, we do know that D2 receptors are decreased by chronic cocaine
administration, and this may induce severe craving for cocaine and possibly
cocaine dreams (Volkow et al. 1993).
A recent study by Ernest Noble of the University of California at Los
Angeles and Blum found that about 52 percent of cocaine addicts have the A1
allele of the dopamine D2 receptor gene, compared to only 21 percent of
nonaddicts. The prevalence of the A1 allele increases significantly with three
risk factors: parental alcoholism and drug abuse; the potency of the cocaine
used by the addict (intranasal versus "crack" cocaine); and
early-childhood deviant behavior, such as conduct disorder. In fact, if the
cocaine addict has three of these risk factors, the prevalence of the A1
allele rises to 87 percent. These findings suggest that childhood behavioral
disorders may signal a genetic predisposition to drug or alcohol addiction
(Noble et al. 1993).
Risk Factors
A recent survey by the National Institute of Drug Abuse of five independent
studies showed that the A1 allele is also associated with polysubstance
dependence (Uhl, Blum, Noble and Smith 1993). The A1 allele is also associated
with an increase in the amount of money spent for drugs by polysubstance-dependent
people (Comings et al. 1994).
Although not viewed in the same light as the use of cocaine and other
illicit drugs, cigarette smoking is another form of chemical addiction. Most
attempts to stop smoking are associated with withdrawal symptoms typical of
the other chemical addictions. Although environmental factors may be important
determinants of cigarette use, there is strong evidence that the acquisition
of the smoking habit and its persistence are strongly influenced by hereditary
factors.
Of particular significance are studies of identical twins, which show that
when one twin smokes, the other tends to smoke. This is not the case in
nonidentical twins. In one twin study, Dorit Carmelli of the Stanford Research
Institute and her associates examined a national sample of male twins who were
veterans of World War II. A unique aspect of this study was that the twins
were surveyed twice, once in 1967-68 and again 16 years later. This allowed an
examination of genetic factors in all aspects of smoking-initiation,
maintenance and quitting. In general, whatever happened to one identical twin
happened to the other-including the long-term pattern of not smoking, smoking
and then quitting smoking. The absence of these similarities in a control
population of nonidentical twins suggests a strong biogenetic component in
smoking behavior (Swan et al. 1990).
Animal studies have suggested that the dopaminergic pathways of the brain
may be involved. For example, the administration of nicotine to rodents
disturbs dopamine metabolism in the reward centers of the brain to a greater
extent than does the administration of alcohol.
With this in mind, one of us (Comings) and his colleagues investigated the
incidence of the A1 allele in a population of Caucasian smokers. These smokers
did not abuse alcohol or other drugs, but had made at least one unsuccessful
attempt to stop smoking. It turned out that 48 percent of the smokers carried
the A1 allele. The higher the prevalence of the A1 allele, the earlier had
been the age of onset of smoking, the greater the amount of smoking and the
greater the difficulty experienced in attempting to stop smoking. In another
sample of Caucasian smokers and nonsmokers, Noble and his colleagues found
that the prevalence of the A1 allele was highest in current smokers, lower in
those who had stopped smoking and lowest in those who had never smoked (Noble et
al. 1994).
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