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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

in a system (e.g. dopamine), which may alter a number of behaviours
including alcohol and tobacco dependence.

Dopamine D1 receptor. As mentioned previously, smoking behaviour (as
defined by the number of cigarettes per day for one year) has been linked to
a genetic location on chromosome 5q (D5S1354) (Duggirala, Almasy
&Blangero, 1999) that is near the dopamine receptor D1 (DRD1) locus. An
association was made between a polymorphism, and smoking, alcohol use,
illicit drug use, compulsive shopping, compulsive eating and gambling
(Comings et al., 1997), although not all studies confirm a role for DRD1 in
alcohol use (Hietala et al., 1997; Sander et al., 1995). These results suggest a
role for genetic variants of the DRD1 gene in some dependence-related
behaviours, and further, suggest an interaction of genetic variants of the DRD1
and DRD2 genes (Comings et al., 1997).

Dopamine D2 receptor. Variants of the dopamine receptor D2 (DRD2) gene
have been associated with dependence on alcohol, nicotine, cocaine and
opioids, and with novelty-seeking, obesity and gambling, but the results have
not been consistent (Noble, 2000; Noble et al., 1998b). It is hypothesized that
the DRD2 gene is involved in reinforcement (see Chapter 3).
Among non-Hispanic Caucasians who smoked at least one pack of
cigarettes per day, had unsuccessfully attempted to stop smoking, and were
not dependent on alcohol or other drugs, the DRD2 A1 allele was more
prevalent than in controls (Comings et al., 1996), although this is not observed
in all studies (Singleton et al., 1998). There was a significant, inverse
relationship between the prevalence of the DRD2 A1 allele and the age of
onset of smoking and the maximum duration of time since the smokers had
quit smoking on their own (Comings et al., 1996). These results support the
concept that the DRD2 gene is one of a multifactorial set of risk factors
associated with smoking (Comings et al., 1996).
In summary, DRD2 may not alter risk for alcohol dependence, but alcohol-
dependent patients with the DRD2 A1 allele may have greater severity of their
disorder across a range of problem drinking indices (Connor et al., 2002).
There are a few examples where the DRD2 genetic variation has been
examined in conjunction with other genes. Variants of both the DRD2 and
GABA receptor subunit β3 genes have been associated with risk for alcohol
A
dependence; however, the risk for alcohol dependence is more robust when
these variants are combined than when they are considered separately (Noble
et al., 1998a). Similarly, DRD2 variant and ADH2 have been shown to have a
stronger association with risk for alcohol dependence when combined than
when alone (Amad et al., 2000).

Dopamine D3 receptor. The DRD3 receptor is found at high levels in the
nucleus accumbens, a region involved in drug reward and dependence (see
Chapter 3). A variant of the DRD3 gene has been shown in some studies to

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