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5. GENETIC BASIS OF SUBSTANCE DEPENDENCE

dependence on other drugs – pointing to components of the endogenous
opioid system as good candidate genes. All three known receptors (mu, delta,
and kappa), and genes coding for opioid ligands have been screened for
genetic variation (Mayer & Hollt, 2001).

Mu opioid receptor

The mu opioid receptor subtype is the primary target of morphine and the
mediator of the reinforcement and reward effect of opioids, which makes
the mu opioid receptor gene the outstanding candidate for genetic
vulnerability. The data however, have not consistently associated this gene
with opioid dependence. Sequencing of the mu opioid receptor gene
identified five single nucleotide polymorphisms (single base pair changes in
nucleotide sequence) in the gene (Bond et al., 1998). However this
polymorphism was not associated with heroin dependence in a sample of
heroin-dependent individuals from China (Li et al., 1997) or Germany (Franke
et al., 2001). However a study among Hong Kong Chinese people found a
significant association (Szeto et al., 2001). Persons expressing a mu opioid
receptor variant have altered hypothalamic–pituitary–adrenal axis function
and altered responses to other physiological processes regulated through
activation of the mu opioid receptor (Wand et al., 2002). Natural sequence
variations in the mu opioid receptor gene have little influence on ligand
binding or receptor down-regulation but could modify receptor density and
signalling (Befort et al., 2001).

Kappa opioid receptor
The kappa opioid receptor has also been examined and positive association
was seen in one study (Mayer et al., 1997), but was not replicated in a second
(Franke et al., 1999). Seven allelic variants in the kappa-1 opioid receptor
gene have been discovered, (LaForge et al., 2000; Mayer & Hollt, 2001), but
there is no evidence that any are functional.

Dopamine D4 receptor
The dopamine D4 receptor (DRD4) has also shown evidence for association
with opioid dependence (Kotler et al., 1997; Li et al., 1997; Vandenbergh et
al., 2000) although this is not supported in another study (Franke et al., 2000).

Prodynorphin
Prodynorphin has also been examined (Zimprich et al., 2000). However,
prodynorphin allelic distributions were not significantly different in people
with heroin dependence and controls.

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