The Dopamine D2 Receptor
The A1 allele carries a behavioral risk factor that shows up not only in substance addiction and attention-deficit disorder, but also in antisocial behavior, conduct disorder and violent or aggressive behavior. In a recent study the A1 allele was present in 60 percent of a sample population of young adolescents between 12 and 18 years old who were diagnosed as "pathologically violent" subjects (Blum Unpublished). A variant of the dopamine transporter gene (VENT 10 repeat) was present in 100 percent of the adolescents. Of these 70 percent had the so-called 10/10 form whereas 30 percent carried the 10/9 allelic form. Another study found that 59 percent of Vietnam veterans with post-traumatic stress disorder also carried the A1 allele, compared to only 5 percent of veterans who were exposed to similar stress but did not develop the disorder (Comings, Muhleman and Gysin 1996).
Why would carriers of the A1 allele be predisposed to the spectrum of disorders associated with the reward deficiency syndrome? Individuals having the A1 allele have approximately 30 percent fewer D2 receptors than those with the A2 allele (Noble et al. 1991). Since the D2 receptor gene controls the production of these receptors, the finding suggests that the A1 allele is responsible for the reduction in receptors. In some way that we do not yet understand, carrying the A1 allele reduces the expression of the D2 gene compared to carrying the A2 allele. Perhaps a regulatory site for the D2 receptor gene is affected in A1 carriers.
D2 Receptor Density
Fewer numbers of dopamine D2 receptors in the brains of A1 allele carriers may translate into lower levels of dopaminergic activity in those parts of the brain involved in reward. A1 carriers may not be sufficiently rewarded by stimuli that A2 carriers find satisfying. This may translate into the persistent cravings or stimulus-seeking behavior of A1 carriers. Moreover, because dopamine is known to reduce stress, individuals who carry the A1 allele may have difficulty coping with the normal pressures of life. In response to stress or cravings, A1 carriers may turn to other substances or activities that release additional quantities of dopamine in an attempt to gain temporary relief. Alcohol, cocaine, marijuana, nicotine and carbohydrates (like chocolate) all cause the release of dopamine in the brain and bring about a temporary relief of craving. These substances can be used singly, in combination or to some extent interchangeably.
Although we believe that the gene for the D2 receptor plays a critical role in reward deficiency syndrome, other genes (such as the dopamine transporter gene) are undoubtedly involved in the different manifestations of the syndrome. Scientists from Israel and the National Institute of Mental Health recently showed that a genetic variation of the dopamine D4 receptor gene is associated with people who are novelty (or sensation) seekers (Ebstein et al. 1996 and Benjamin et al. 1996). Both studies set out to test the hypothesis advanced by Robert Cloninger of Washington University that novelty-seeking behavior is modulated by the way brain cells process dopamine. Richard Ebstein and his colleagues at the Herzog Memorial Hospital in Jerusalem found that novelty seekers-who tended to be compulsive, exploratory, fickle, excitable, quick-tempered and extravagant-were much more likely to have a longer version of the receptor gene than individuals who were not novelty seekers. Subjects with the shorter version of the gene scored lower on test of novelty seeking and tended to be reflective, rigid, loyal, stoic, slow-tempered and frugal. Jonathan Benjamin and his colleagues found similar results in their sample of 315 American subjects.
The work from the laboratories of Benjamin and Ebstein provide support of the earlier work of Susan George and associates at the University of Toronto who found a strong association between variants of the D4 gene and alcoholism and nicotine dependence. The D2 receptor gene and the D4 receptor gene have fairly similar nucleotide sequences and may have similar physiological functions. In this respect, it is intriguing that investigators at the University of California, Los Angeles found an association between the A1 allele and individuals who were classified as "sensation seekers" and were characterized by agitation, impulsivity, excitability and a "hot temper" (Compton et al. unpublished). All of these studies further support a connection between the reward deficiency syndrome and the dopaminergic system.
