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Chapter 2
2.2c The dopamine transporter genotype (DAT1/SLC6A3)
One way to account for inter-individual differences in dopamine function is by taking into
account natural variation in the dopamine transporter (DAT) genotype (
DAT1/SLC6A3)
.
Within this gene, short sequences of DNA are repeated (in tandem), and the number of
times this repetition occurs varies across participants (i.e. is polymorphic). When assessing
variation in the variable number of tandem repeats (VNTR) in a particular part of the
DAT gene, the 3’untranslated region (UTR), people can have between 3 and 11 repeats of
the gene, but the 9-repeat (9R) and 10-repeat (10R) are most common and thus often the
focus of research.
Variation in this polymorphismhas been used to assess whether drug and/or task effects are
dopamine-dependent. However, the effect of having either of the VNTRs on the baseline
levels of dopamine is still under debate.
In vitro
studies have shown that the VNTR has an
effect on DAT expression and that the 10R allele is associated with higher expression (Fuke
et al., 2001). A number of
in vivo
studies have used single photon emission computed
tomography (SPECT) to assess DAT-density in human subjects.The results are inconsistent
(
table
), but those with the largest sample of healthy subjects suggest that (healthy) humans
carrying the 9R allele may have upregulated DAT. However, the next question then is how
these inter-individual differences in DAT expression relate to differences in dopamine
signalling. The SPECT studies measure DAT binding, reflecting howmuch DAT is present,
and do not measure any differences in dopamine levels or dopamine release. The DAT is
highly adaptive to homeostatic needs; it is thus possible that subjects with higher phasic
dopamine levels will have upregulated DATs to terminate dopamine’s action after it has
been released.
Although the effects of either carrying at least on 9-repeat allele (9R+), of two 10-repeat
alleles (10R/10R)
DAT1
genotype are to be determined, we do consistently see effects of
the
DAT1
on behaviour and neural responses. For example, variability in the
DAT1
gene
predicted reward-related activity in ventral striatum (Dreher et al., 2009; Forbes et al., 2009;
Aarts et al., 2010). In line with the hypothesized increase in phasic dopamine signalling in
individuals who carry at least one 9 repeat allele, these studies revealed increased neural
activity (measured with fMRI) in the ventral striatum in individuals carrier 9 repeats of the
allele (compared with 10R homozygotes) during reward processing.