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5. GENETIC BASIS OF SUBSTANCE DEPENDENCE

for acute effects of alcohol is located on mouse chromosome 11 and encodes
the GABA receptor γ2, α1, α6, and β2 subunits, suggesting a role for these
A
subunits in response to alcohol (Hood & Buck, 2000). A GABA receptor variant
A
a6 subunit segregates in a rat line which voluntarily avoids alcohol
consumption, providing support for a possible role for variants of this
receptor subtype to alter genetic predisposition to alcohol preference (Saba
et al., 2001). Different variants of the α6 subunit are associated with lower
alcohol response (Iwata, Virkkunen & Goldman, 2000), alcohol dependence
(Loh et al., 2000) and with Korsakoff’s psychosis (Loh et al., 1999).

GABA receptor β1. GABA receptor β1 gene variants were associated with
A A
alcohol dependence (Parsian & Zhang, 1999).
GABA receptor β2. GABA receptor β2 variants were tested and found not to
A A
associate with alcohol dependence or alcohol withdrawal (Sander et al.,
1999a). The BanI RFLP at the GABA β2 receptor subunit gene associated with
A
both alcohol dependence and Korsakoff’s psychosis (Loh et al., 1999).

GABA receptor β3. An association of GABA receptor β3 variants was found
A A
with severe alcohol dependence (Noble et al., 1998a).
GABA receptor γ2. Functionally relevant variation in GABA γ2, or a closely
A A
linked gene, is correlated genetically with some behavioural responses to
alcohol in certain strains of mice (Hood & Buck, 2000). No association in
humans has been found (Hsu et al., 1998; Sander et al., 1999a), except in the
presence of antisocial personality disorder (see Box 6.1) (Loh et al, 2000).

GABA receptor R1. Data suggest that GABA R1 variants do not contribute a
B B
substantial effect to the genetic variance of alcohol dependence (Sander et
al., 1999b). Nevertheless, possible evidence of potential allelic associations
emphasize the need for further studies to test more defined phenotype–
genotype relationships.

Dopamine system
Because of its importance in brain reward circuits, the mesolimbic
dopaminergic system has been implicated in the reinforcing effects of many
substances including nicotine and ethanol (Uhl et al., 1998; Merlo Pich,
Chiamulera & Carboni, 1999; Comings & Blum, 2000) (see also Chapter 3).
Accordingly, polymorphisms of genes in the dopaminergic system are
plausible functional candidate genes for tobacco and alcohol dependence.
Studies over the past decade have shown that alleles of the dopamine receptor
system are associated with alcohol and tobacco dependence, dependence
on other psychoactive substances, novelty-seeking, obesity, compulsive
gambling and several personality traits. This is an example of genetic variation

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