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.

fMRI activation during response inhibition and error processing: The role of the DAT1 gene in typically developing adolescents and those diagnosed with ADHD

“…Langleben et al, 2002). Our results are broadly consistent with those of a recent study by Bédard et al, 2009, where a two-week stimulant withdrawal period was used.…”

“…Durston et al, 2008; also see Bédard et al, 2009). During successful inhibitions, there was increased activation for the HRgenotype in the right middle frontal gyrus, the ACC and caudate, as well as the right middle temporal and middle occipital gyri, while there was reduced activation in the left inferior temporal gyrus.…”

Comparison of Clinical Characteristics of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections and Childhood Obsessive-Compulsive Disorder

“…comm., 2010). Also, neuroimaging studies suggest that dopaminergic and volumetric abnormalities in the striatum may play a role in symptoms of hyperactivity and impulsivity (Carmona et al 2009;Bédard et al 2010).…”

Effects of dopaminergic genes, prenatal adversities, and their interaction on attention-deficit/hyperactivity disorder and neural correlates of response inhibition

“…16 Neuroimaging studies have indicated that children with ADHD homozygous for the DAT1 3' UTR 10R risk allele have reduced volumes of the caudate nucleus and lowered neural activation of this region during response inhibition. 17,18 However, some reports have claimed effects of DAT1 on the caudate nucleus and cortical regions involved in response inhibition in the opposite direction, 19 suggesting that its effects on brain and behaviour may depend on other factors.…”