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5. GENETIC BASIS OF SUBSTANCE DEPENDENCE

may contribute to the amount of alcohol intake, not only in people with
alcohol dependence, but also in a general male population. Visual and
auditory disturbances among people with alcohol dependence in withdrawal
symptoms were significantly different among COMT genotypes (Nakamura
et al., 2001), suggesting that COMT activity could partially affect the
appearance of delirium tremens in these individuals.

Tyrosine Hydroxylase. Tyrosine hydroxylase (TH) is the rate-limiting enzyme
in the biosynthesis of catecholamines. Nicotine has been shown to regulate
TH, and mice with more TH are less sensitive to nicotine. No association was
found between a TH genetic polymorphism and cigarette smoking (Lerman
et al., 1997).
Results to date suggest that no major influence on alcohol dependence is
exerted through genes associated with the TH variants (Geijer et al., 1997;
Ishiguro et al., 1998; Albanese et al., 2001).

Serotonergic systems
Genes in the serotonin system are plausible candidates for association with
smoking or alcohol dependence because of the role of serotonin in mood
regulation, impulse control, appetite and aggression (Veenstra-VanderWeele
et al., 2000). Nicotine can increase serotonin release suggesting that some
aspects of smoking might be altered by variation in the serotonergic system
(e.g. variable mood disturbances during withdrawal resulting in altered
cessation rates). In addition, a number of serotonin reuptake inhibitors are
being examined for their utility in smoking cessation and in preventing weight
gain associated with smoking cessation. Alterations in the serotonergic
neurotransmission have been frequently described for patients suffering from
alcohol dependence, anxiety disorders and narcolepsy, thus the serotonergic
system provides additional candidate genes for genetic variation in alcohol
dependence and smoking.

Serotonin receptors. While functional polymorphisms have been identified
in serotonin receptors and associated with relevant personality dimensions
(e.g. harm-avoidance, reward dependence), there are no reports of
associations between serotonin receptors and smoking behaviour. In the
studies of serotonin receptor variants and alcohol dependence there are some
positive and many negative findings (Yoshihara et al., 2000b). A clearer
phenotype, including personality variables, may be required before a better
picture of the role of serotonin receptors in the genetic risk for alcohol-related
behaviours can be elucidated.

Serotonin Receptor 1B. The 5HT1B receptor gene variant (G861C) has not been
associated with alcohol dependence (Gorwood et al., 2002; Kranzler et al.,
2002), either alone or with a comorbid antisocial diagnosis (Kranzler et al.,

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