Dopamine transporter
The gene for DAT, known as DAT1, is located on chromosome 5p15. The protein-encoding region of the gene is more than 64 kb long and includes 15 coding segments or exons. This gene has a variable number tandem repeat (VNTR) at the 3′ end (rs28363170) and another in the intron 8 region. Differences in the VNTR have been shown to affect the basal level of expression of the transporter; as a consequence, researchers have looked for associations with dopamine-related disorders. Hill et al16 investigated the relative activity of VNTR alleles of SLC6A (dopamine transporter) under basal and stimulated cellular conditions, as well as in the presence of a pharmacologic blockade of the dopamine transporter. They reported that the intron 8 VNTR 5-repeat allele was more active than the 6-repeat allele and concluded that the intron 8 VNTR is a functional variant ADHD susceptibility allele with reduced activity. An association between DAT1 and ADHD has been reported by a number of investigators.17–19
Bellgrove et al20 investigated sustained attention response variability and attentional bias in 27 right-handed children and adolescents diagnosed with ADHD and 20 right-handed controls.20 They used a Landmark grayscales task, shaded from pure black to pure white, to assess perceptual bias, and a fixed-sequence sustained attention task21 to investigate response variability. DAT1 genotyping indicated that only 9% of ADHD probands did not possess a 10-repeat allele, 45% were heterozygous, and 45% were homozygous.21 The investigators grouped the ADHD cohort as high risk (two 10-repeat alleles) and low risk (one or no copies of 10-repeat alleles). ADHD symptomatology measured dimensionally was correlated with a Landmark Asymmetry index, showing that left-sided inattention was correlated with inattentive symptoms. A significant effect of the DAT1 genotype group was found for right spatial bias/left-sided inattention. The Landmark Asymmetry index significantly predicted biased parental transmission of high-risk versus low-risk parental alleles. Finally, an analysis of methylphenidate (MPH) medication response showed that the high-risk DAT1/very good response group displayed left-sided inattention, although the low-risk DAT1/mediocre response group also showed a small leftward bias. The investigators proposed that increased transporter activity would result in reduced extracellular dopamine within right hemisphere attentional networks. Treatment with MPH was thought to inhibit the transporter and restore dopaminergic balance in spatial attentional systems.
Bellgrove et al22 investigated the relationship between spatial inattention measured on the Landmark Task and the DAT1 3′ variable number of tandem repeat polymorphism in 43 ADHD children and their parents. Children who were rated by their parents as showing a good response to MPH displayed left-sided inattention, whereas children with a poor response did not, replicating the above smaller study. In addition, left-sided inattention predicted transmission of the 10-repeat DAT allele from parents to probands.
Tomasi et al23 investigated the relationship between dopamine transporters in the striatum and the default mode network (DMN) during visuospatial attention. They used positron emission tomography scans with a cocaine radiotracer to estimate DAT availability and functional magnetic resonance imaging (fMRI) during a parametric visual attention task. The investigators hypothesized that higher DAT levels would result in a lower concentration of extracellular dopamine, reducing the availability to deactivate the DMN during the visual attention task. Higher DAT was thought to result in activation, rather than deactivation, of DMN and greater activation of compensatory dorsal network regions. Fourteen healthy nonsmoking adult men were investigated. The results indicated that DAT availability in the caudate showed positive correlations with blood-oxygen-level-dependent signals in right postcentral gyrus, bilateral superior parietal lobe, left ventral precuneus, and left thalamus, and negative correlations with signals in right perigenual anterior cingulated gyrus (although thalamus correlations were not significant after the removal of an outlier). According to the investigators, the study showed that most of the correlations with DAT occurred in areas deactivated by the task, implying that greater DAT levels were associated with less deactivation. The study is important in suggesting that the beneficial effects of stimulant medications (one of the actions of which is to block DAT) might be manifested through deactivation of the DMN. A longer-lasting presence of dopamine in patients with low DAT might ensure longer-lasting interest and attention to relevant stimuli.
Kambeitz et al24 reported results of a meta-analysis that investigated the moderating effect of SLC6A3 VNTR on response to methylphenidate treatment in 16 studies including 1,572 subjects. They found no significant summary effect, although 10R homozygotes showed less improvement than non-10/10 carriers. The authors questioned whether other genetic polymorphisms or nongenetic factors might be important. Braet et al25 showed that possession of a “high-risk” 10-repeat DAT1 allele was associated with decreased activation in parietal and prefrontal brain regions during response inhibition and in frontal and medial brain regions on error trials in a go-no-go task.
Cummins et al26 investigated the association of allelic variation in polymorphisms of the dopamine transporter gene (SLC6A3: rs37020: rs 46000). They used a stop-signal task that measured inhibition of response by stop-signal delay. Delay times were set relative to individuals’ mean response time to ensure approximately 50% of delay times. fMRI was carried out to assess brain activity during response inhibition and correlated with the genetic polymorphisms mentioned earlier. The author found evidence of association among SLC6A3 variants, rs 37020b and rs 460000, and measures of response speed and reaction time variability.
Cummins et al26 also conducted an fMRI analysis on “successful inhibition-go” trials to assess the effect of genotype on brain activity associated with inhibition (longer stop-signal response times [SSRTs]). An association between SLC6A3 rs 37020 and SSRT was demonstrated at the corrected level. The T allele was coded as 0, 1, and 2 (GG, GT, and TT), respectively. The fMRI results showed that activity in the caudate nucleus and frontal regions increased additively for the TT to GT to GG genotype of rs 37020, with patients with the poorest inhibitory ability (TT genotype) showing the least inhibitory activity in inhibition networks. The authors concluded that the influence of genetic variation in SLC6A3 might represent a key risk mechanism for disorders of behavioral inhibition. Thus, many studies point to the 10R DAT allele as a risk allele for diagnosis.