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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Dopamine beta hydroxylase. Smokers with a particular dopamine beta
hydroxylase (DBH) genotype smoked fewer cigarettes when compared to
those without the genotype (McKinney et al., 2000). Heavy smokers
(>20 cigarettes per day) had a higher frequency of the DBH variant allele when
compared to light smokers (McKinney et al., 2000).

Monoamine Oxidase A. Central dopaminergic reward pathways give rise to
dependence and are activated by nicotine and alcohol indicating that allelic
variants in genes involved in dopamine metabolism may be important in
dependence. Monoamine oxidase (MAO) is involved in the metabolism of
neurotransmitters including dopamine, serotonin and norepinephrine. There
are two distinct forms of MAO: MAO-A and MAO-B; both are encoded in genes
on the X chromosome.
MAO activity is reduced by smoking (Checkoway et al., 1998). One study
found that smokers with a certain MAO-A genotype smoked more cigarettes
than those without that genotype (McKinney et al., 2000).
Low platelet MAO activity has been associated with alcohol dependence,
making genetic variation in these genes of interest. Variations in the MAO-A
and MAO-B genes differ between people with alcohol dependence and
controls (Parsian et al., 1995). A variant of the MAO-A gene is associated with
both a risk for alcohol dependence and lower age of onset of substance
dependence in males (Vanyukov et al., 1995).
Significant associations of alcohol dependence with MAO-A alleles were
found among the Han Chinese people, but not among aboriginal Taiwanese
groups (Hsu et al., 1996). A functional polymorphism in the MAO-A allele
was identified and the frequency was increased in males with antisocial
personality disorder and alcohol dependence, but not in those with alcohol
dependence alone or in controls (Samochowiec et al., 1999; Schmidt et al.,
2000).

Catechol-O-methyltransferase. Catechol-O-methyltransferase (COMT)
inactivates catecholamines and catechol drugs. A common genetic
polymorphism in humans is associated with a 3–4 fold variation in COMT
enzyme activity (Lachman et al., 1996). Since ethanol and nicotine use are
associated with rapid release of dopamine in limbic areas, it is conceivable
that subjects who inherit low activity alleles would inactivate dopamine more
slowly, thereby altering their vulnerability to the development of dependence.
A functional polymorphism resulting in increased enzyme activity has been
associated with alcohol dependence and polysubstance use (Vandenbergh
et al., 1997; Horowitz et al, 2000). No association was found between this
COMT polymorphism and smoking initiation, smoking persistence and
smoking cessation (David et al., 2002).
Men with a specific COMT genotype (30% of all subjects) reported 27%
higher weekly alcohol consumption compared with the two other genotype
groups (Kauhanen et al., 2000). The results indicate that COMT polymorphism

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