Dopamine transporter gene variation modulates activation of striatum in youth with ADHD

Abstract

Polymorphisms in the 3'UTR variable number tandem repeat (VNTR) of exon 15 of the dopamine transporter gene (DAT1) have been linked to attention-deficit hyperactivity disorder (ADHD); moreover, variability in DAT1 3'UTR genotype may contribute to both heterogeneity of the ADHD phenotype and differences in response to stimulant medications. The impact of this VNTR on neuronal function in individuals with ADHD remains unclear despite evidence that the polymorphisms influence dopamine transporter expression. Thus, we used event-related functional magnetic resonance imaging to examine the impact of DAT1 3'UTR genotype on brain activation during response inhibition in unmedicated children and adolescents with ADHD. Twenty-one youth with ADHD who were homozygous for the 10-repeat (10R) allele of the DAT1 3'UTR and 12 youth who were carriers of the 9-repeat (9R) allele were scanned while they performed a Go/No-Go task. Response inhibition was modeled by contrasting activation during correct No-Go trials versus correct Go trials. Participants who were homozygous for the DAT1 3'UTR 10R allele and those who had a single 9R allele did not differ on percent of trials with successful inhibition, which was the primary measure of inhibitory control. Yet, youth with the DAT1 3'UTR 10R/10R genotype had significantly greater inhibitory control-related activation than those with one 9R allele in the left striatum, right dorsal premotor cortex, and bilaterally in the temporoparietal cortical junction. These findings provide preliminary evidence that neural activity related to inhibitory control may differ as a function of DAT1 3'UTR genotype in youth with ADHD.

Fig. 1

Schematic diagram of the Go/No-Go task. The diagram illustrates a No-Go trial (Green Goblin) preceded by three Go trials (Spiderman). Stimuli were presented individually at fixation for 500ms, followed by a 3500ms interstimulus interval demarcated by a small spider. Trial order was pseudorandomized so that the occurrence of No-Go trials was jittered from 4 to 20 seconds (i.e., preceded by 1 to 5 Go trials). Participants were instructed to “press the button for all Spiderman pictures and not press for Green Goblin.” The images of Spiderman and Green Goblin were adapted from promotional images for the “Spiderman” movie (^©Columbia Pictures Industries, Inc.).

Fig. 2

Regions showing significant differences in BOLD responses to successful response inhibition (correct No-Go events minus correct Go events) in youth with attention-deficit hyperactivity disorder (ADHD) who were homozygous for the DAT1 3′UTR 10-repeat (10R) allele compared to those who are heterozygous for the 9-repeat (9R) allele. Arrows indicate the temporoparietal cortical junction (left section), striatum (middle section), and inferior frontal gyrus (right section). The activations were significant at p < 0.05 corrected with a voxel extent > 100 voxels. The inset depicts the position and Talairach coordinates for the sections.

Fig. 3

Percent BOLD signal change in the striatum for successful response inhibition. Bars represent mean signal change for correct No-Go and Go events in youth with attention-deficit hyperactivity disorder (ADHD) who were homozygous for the DAT1 3′UTR 10-repeat (10R) allele versus those heterozygous for the 9-repeat (9R) allele. Error bars represent ± 1 standard error.