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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

excretion is increased, and smoking is decreased if nicotine is administered
concurrently either intravenously or with a patch. The genes involved in
nicotine metabolism may be important risk factors for smoking; the extent
of variation is likely to be a major determinant of levels and accumulation of
nicotine in the brain.
The metabolic enzyme CYP2A6 is genetically polymorphic (i.e. exists in
more than one form). It is responsible for about 90% of the metabolic
inactivation of nicotine to cotinine (Nakajima et al., 1996; Messina, Tyndale
& Sellers, 1997). A significant impact of CYP2A6 genetic variance has been
found on the risk for tobacco dependence, age of starting smoking, the
amount and patterns of cigarette smoking, duration of smoking, probability
of quitting, and some aspects of risk of developing lung cancer (Miyamoto et
al., 1999; Gu et al., 2000; Rao et al., 2000; Tyndale et al., 2002; Tyndale & Sellers,
2002). However, not all studies agree with these findings (Loriot et al., 2001;
Tiihonen et al., 2000; Zhang et al., 2001).
Among Caucasian smokers those with genetically slow nicotine metabolism
required fewer cigarettes per day, reflected in lower carbon monoxide levels,
to maintain equal plasma nicotine levels, while those with the CYP2A6 gene
duplication (fast metabolizers) smoked more, and with greater intensity (Rao
et al., 2000). In Caucasians, frequencies of genotypes with at least one decreased
or inactive allele were higher in non-smokers than in smokers (Tyndale et al.,
2002) indicating that slow nicotine inactivation modestly protects people from
becoming smokers. It has also been shown that inhibiting CYP2A6 (mimicking
the genetic defect) in smokers results in decreased smoking and rerouting of
procarcinogens to other detoxifying pathways (Sellers, Kaplan & Tyndale, 2000;
Sellers et al., 2002). Substantial variation in CYP2A6 allele and genotype
frequencies exists among ethnic groups (Oscarson et al., 1999; Tyndale et al.,
2002). These data suggest that the CYP2A6 genotype is likely to alter the risk for
smoking and may alter the risk for smoking-related disease (Bartsch et al., 2000)
among ethnic groups.

Genetics of alcohol dependence
Heritability of alcohol dependence

Heritability estimates of alcohol dependence depending on the diagnostic
criteria used (e.g. DSM-IV, ICD-10; see Boxes 1.2 and 1.3) range from 52% to
63% (van den Bree et al., 1998a). It seems that some diagnostic systems are
more sensitive in detecting genetic influences and may be more appropriate
for studies attempting to find genes for alcohol dependence (van den Bree et
al., 1998a).
Twin studies provide estimations of the heritability of predisposition to
alcohol dependence of 51–65% in females and 48–73% in males (Carmelli et
al., 1992; Kendler et al., 1994; Heath et al., 1997; Johnson et al., 1998; Han et
al., 1999a; Prescott, Aggen & Kendler, 1999; Prescott & Kendler, 1999; Enoch

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