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5. GENETIC BASIS OF SUBSTANCE DEPENDENCE

(Box 1.2). Thus, it can be seen that there are multiple genetic factors (as well
as environmental factors such as availability and marketing) that contribute
at different stages in the development of dependence.

Tobacco dependence and linkage studies
There is some evidence that smoking behaviour is associated with at least
14 different chromosomal locations (Bergen et al., 1999; Duggirala, Almasy
& Blangero, 1999; Straub et al., 1999;). These studies suggest that the effect of
any one gene on smoking behaviour is likely to be weak (Bergen et al., 1999;
Arinami et al., 2000; Duggirala, Almasy & Blangero, 1999). One of the loci of
interest is located on chromosome 5q near the locus for the dopamine D1
receptor, and this receptor has been associated with smoking (Comings et
al., 1997; Duggirala, Almasy & Blangero, 1999).

Candidate genes for tobacco dependence
Nicotine is the primary compound in tobacco that establishes and maintains
tobacco dependence (Henningfield, Miyasato & Jasinski, 1985). Smokers who
are dependent on tobacco adjust their smoking to maintain their nicotine
levels (Russell, 1987). Studies have been carried out to examine if genetic
variation in the specific receptors for nicotine (Mihailescu & Drucker-Colin,
2000) as well as in pathways of nicotine elimination (Tyndale & Sellers, 2002)
alter aspects of smoking behaviour.

Nicotinic receptors
Several types of evidence have suggested that a nicotinic receptor containing
the β2-subunit is necessary for at least some of the reinforcing properties of
nicotine (Mihailescu & Druker-Colin, 2000). However, no associations with
changes in these receptors have been found (Silverman et al., 2000).
Recent studies of ethanol and tobacco use by humans suggest that
common genes may influence the dependence on tobacco and ethanol. The
results of one study of inbred mouse strains, selected on the basis of their
response to ethanol, suggest that the α4 nicotinic receptor gene should be
evaluated for its potential role in regulating ethanol and tobacco use in
humans (Tritto et al., 2001).

Nicotine metabolism
Variation in the metabolic inactivation of nicotine is important because of
the role of nicotine in producing tobacco dependence and regulating smoking
patterns (Henningfield, Miyasato & Jasinski, 1985; Russel, 1987). Smoking is
increased if the nicotine content in cigarettes is decreased or if nicotine

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