Proefschrift_Holstein

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.

38