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5. GENETIC BASIS OF SUBSTANCE DEPENDENCE

alter function. The role of this variant in tobacco smoking has not been
studied, but it has been shown to alter use of some other substances and
psychiatric disorders. Studies of DRD3 and alcohol dependence
demonstrated no significant association (Parsian et al., 1997; Henderson et
al., 2000).

Dopamine D4 receptor. A variant of the DRD4 gene has been identified and is
thought to play a role in nicotine dependence. When exposed to smoking
cues before smoking either high-nicotine cigarettes or control cigarettes,
individuals with the DRD4 variant allele had greater craving, more arousal,
less positive affect, and more attention to the smoking cues than did those
without the variant allele (Hutchison et al., 2002a). These preliminary results
suggest that the rewarding effects of smoking and the beneficial effects of
nicotine replacement therapy may depend, in part, on genetic factors
involved in dopamine transmission.
An association study on the DRD4 gene showed that African-Americans
who had at least one variant allele had a higher risk of smoking, a shorter
time to the first cigarette in the morning, and an earlier age at smoking
initiation (Shields et al., 1998). After smoking cessation counselling, none of
the smokers with the variant allele were abstinent at 2 months, compared
with 35% of the smokers who were homozygous for the non-variant genotype.
The analysis of Caucasians did not suggest a similar risk.
Some studies have shown an association between alcohol dependence and
DRD4 receptor variation (George et al., 1993; Hutchison et al., 2002b), while
others have not (Parsian et al., 1997; Ishiguro et al., 2000; Albanese et al., 2001).
It is interesting that the DRD4 variation increased the risk for alcohol
dependence in individuals with protective ALDH2*2 variants, indicating the
overriding of the protective effects of ALDH2*2 by the DRD4 variant
(Muramatsu et al., 1996).

Dopamine D5 receptor. Several functional polymorphisms in DRD5 have been
identified (Cravchik & Gejman, 1999); however, for smoking initiation, there
was no significant association with the four DRD5 markers studied. While
these data are not consistent with a strong role for DRD5 in the etiology of
smoking behaviours, one study suggested the involvement of the locus in
the variation of risk of substance use and antisocial behaviour (Vanyukov et
al., 2000), indicating that further studies may be warranted.

Dopamine transporter. A polymorphism of the dopamine transporter has
been identified which can alter rates of transcription (production of
messenger RNA, mRNA) (Michelhaugh et al., 2001) and which is associated
with altered levels of the dopamine transporter protein in the brain (Heinz et
al., 2000), suggesting that the polymorphism results in functional differences.
However, no association with substance dependence has been found.

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