Page 159 - Pagetit

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

CYP2D6
Opioid metabolizing enzymes are also strong candidate genes for involvement
in susceptibility. The most significant finding in opioid dependence is the
association found between oral codeine dependence and the metabolizing
enzyme CYP2D6 (Tyndale, Droll & Sellers, 1997). Many opioids (e.g. codeine,
oxycodone and hydrocodone) are metabolized by CYP2D6 to metabolites of
increased activity, principally morphine. It is estimated that 4–10% of
Caucasians lack CYP2D6 activity due to inheritance of two non-functional
alleles. Tyndale, Droll & Sellers (1997) found that of a group of people with
dependence on oral opiates, there were no poor metabolizers of CYP2D6
(Fisher’s exact test, p < or = 0.05). This is in contrast with 4% of people in the
non-dependent group being poor metabolizers of CYP2D6, suggesting that the
CYP2D6 variant genotype offers protection against oral opioid dependence.
However, this finding remains controversial (Mikus et al., 1998).

Genetics of the combined risk of dependence on tobacco,
alcohol, opioids and other psychoactive substances
Heritability of substance dependence
Genetic risk influences the predisposition to use and to the development of
dependence on alcohol, tobacco and opioids individually. However, there is
also a genetic contribution to use of, and dependence on, a combination of
alcohol, tobacco and other substances (Carmelli et al., 1992; Reed et al., 1994;
Swan, Carmelli & Cardon, 1996, 1997; Daeppen et al., 2000; Hopfer, Stallings
& Hewitt, 2001; Tsuang et al., 2001).
The classic adoption studies of Cadoret have been instrumental in defining
the importance of genetic factors in substance abuse (Cadoret et al., 1986,
1995). These studies demonstrated that substance abuse was significantly
greater in adoptees whose biological parents were dependent on alcohol or
other psychoactive substances, or who had a personality disorder. This led
to a model in which two genetic factors and an independent, environmental
factor from the adoptive family increase the risk of substance abuse.
The co-occurrence of lifetime tobacco and alcohol dependence has a
substantial genetic correlation suggesting a common genetic vulnerability
(True et al., 1999). Environmental features have a large influence on the
initiation of alcohol and tobacco use in adolescents, whereas alcohol and
tobacco use in slightly older young adults was more influenced by genetic
risk factors (Koopmans, van Doornen & Boomsma, 1997). People who smoke
are also at greater risk for severe alcohol dependence (Daeppen et al., 2000).
Significant genetic correlations exist between problem drinking and ever
smoking or using at least one half-pack (10 cigarettes) per day (Hopfer,
Stallings & Hewitt, 2001). The shared genetic influence on alcohol use and
smoking in women is clearest for those subjects with the highest severity of
alcohol use (Hopfer, Stallings & Hewitt, 2001).

138

Chapter_5 138 19.1.2004, 11:45