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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Candidate genes involved in substance dependence
Candidate gene studies examine alleles that might reasonably be thought to
be involved in a disorder. Currently the best candidate allelic variants fulfil at
least two criteria: the variant has been shown to alter function, and the variant
has a good likelihood of being biologically relevant (Stoltenberg & Burmeister,
2000).
There are two main types of genes that have been associated with drug
dependence; those that are likely to be specific to the particular dependence
[e.g. nicotinic receptors and smoking, ethanol metabolism and alcohol
dependence (Grant et al., 1999)] and those that may play a common role in
either all or a subset of dependencies. Genetic alterations in various
combinations of the genes for neurotransmitters and receptors (i.e. serotonin,
norepinephrine, GABA, glutamate and opioid) that modify dopamine neuron
function may put individuals at risk for dependence (Comings & Blum, 2000;
Quattrocki, Baird & Yurgelun-Todd, 2000). Like other behavioural disorders,
substance dependence is polygenically (i.e. many genes) inherited and each
gene is likely to account for only a small percentage of the variance. In each
subsequent section, gene candidates that may affect dependence more
generally will follow the candidate genes specific to tobacco, alcohol and
opioid dependence.

GABAergic systems

Inhibition of GABAergic systems in the substantia nigra fine-tunes the amount
of dopamine released at the nucleus accumbens, an important site for the
effects of all psychoactive substances (see Chapters 3 and 4). GABA receptor
A
blockers reduce some ethanol-induced behaviours, such as motor
impairment and sedation. The role of this receptor in alcohol dependence is
further supported by effective alleviation of alcohol withdrawal symptoms
by GABA agonists (Parsian & Cloninger, 1997). In addition, one of the clusters
A
of GABA receptors is located on chromosome 4, at a locus which is thought
A
to feature prominently in alcohol dependence. Thus the GABAergic system
may alter risk for smoking and alcohol dependence (Loh & Ball, 2000).
Nicotine can stimulate the firing rate of dopamine neurons in the ventral
tegmental area (VTA), but GABAergic neurons may also be an important target
for the effects of nicotine on the central nervous system.

GABA receptor α1. No association has been found with any type of substance
A
dependence (Parsian & Cloninger, 1997).
GABA receptor α3. An association was found for alcohol dependence, but
A
not with its subtypes (Parsian & Cloninger, 1997).

GABA receptor α6. There is some evidence for the involvement of this receptor
A
subunit in alcohol dependence, in both animal and human studies. A locus

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