Methylphenidate Effects on Brain Activity as a Function of SLC6A3 Genotype and Striatal Dopamine Transporter Availability

Abstract

We pharmacologically challenged catecholamine reuptake, using methylphenidate, to investigate its effects on brain activity during a motor response inhibition task as a function of the 3 0 -UTR variable number of tandem repeats (VNTR) polymorphism of the dopamine transporter (DAT) gene (SLC6A3) and the availability of DATs in the striatum. We measured the cerebral hemodynamic response of 50 healthy males during a Go/No-Go task, a measure of cognitive control, under the influence of 40 mg methylphenidate and placebo using 3T functional magnetic resonance imaging. Subjects were grouped into 9-repeat (9R) carriers and 10/10 homozygotes on the basis of the SLC6A3 VNTR. During successful no-go trials compared with oddball trials, methylphenidate induced an increase of blood oxygen level-dependent (BOLD) signal for carriers of the SLC6A3 9R allele but a decrease in 10/10 homozygotes in a thalamocortical network. The same pattern was observed in caudate and inferior frontal gyrus when successful no-go trials were compared with successful go trials. We additionally investigated in a subset of 35 participants whether baseline striatal DAT availability, ascertained with 123 I-FP-CIT single photon emission computed tomography, predicted the amount of methylphenidate-induced change in hemodynamic response or behavior. Striatal DAT availability was nominally greater in 9R carriers compared with 10/10 homozygotes (d ¼ 0.40), in line with metaanalyses, but did not predict BOLD or behavioral changes following MPH administration. We conclude that the effects of acute MPH administration on brain activation are dependent on DAT genotype, with 9R carriers showing enhanced BOLD following administration of a prodopaminergic compound.

Association of COMT and SLC6A3 polymorphisms with impulsivity, response inhibition and brain function

“…For example, a qualitatively similar pattern was found during reward anticipation and memory in the striatum and hippocampus, respectively (Wittmann, Tan, Lisman, Dolan, & Dü zel, 2013). Additionally, in a pharmacogenetic study of the moderating role of SLC6A3 in the effects of methylphenidate on brain function during go/no-go task performance we recently observed in an independent sample, using the same task as in the current study, that 10R homozygotes had higher BOLD than 9R carriers in an extended cortico-subcortical network in the placebo condition (Kasparbauer et al, 2015), compatible with the current findings.…”

“…Therefore, and in the absence of a measure for DAT availability, our interpretations remain speculative and other levels of explanation, such as the role of effort (Braet et al, 2011), may also need to be considered. However, based on the findings of two independent meta-analyses that associated 10R carriers with lower DAT (Costa et al, 2011;Faraone et al, 2014) and our recent study confirming this pattern with a medium effect size in a new sample (Kasparbauer et al, 2015), future studies combining genetic and molecular imaging methods might further elucidate our interpretations. A second limitation concerns the sample size in the respective genotype groups.…”

“…Due to the smaller sample size of Experiment 2, SLC6A3 9/9 homozygotes and 9/10 heterozygotes were grouped together into a group of 9R carriers, as done previously (Costa et al, 2011;Kasparbauer et al, 2015). As in Experiment 1, statistical effects of genotype on demographic variables were assessed using one-way analysis of variance (ANOVA) or c 2 tests as appropriate.…”

“…Importantly, some of the studies with negative findings at the level of inhibitory performance found associations between neural activation during inhibition and the COMT or SLC6A3 polymorphisms (Congdon et al, 2009;Ettinger et al, 2008;Kasparbauer et al, 2015;Stokes et al, 2011), suggesting that the investigation of brain function may be a more powerful method for the detection of gene effects than the study of behavioural measures alone (Meyer-Lindenberg & Weinberger, 2006). Therefore, in Experiment 2 we used fMRI to investigate the associations of these two polymorphisms with BOLD during the antisaccade, go/no-go and stop-signal tasks.…”

“…However, several imaging studies confirm the existence of modulatory effects of SLC6A3 genotype in non-striatal areas (Arnold et al, 2015;Bertolino et al, 2009;Braet et al, 2011;Dreher et al, 2009;Kasparbauer et al, 2015). It has been suggested that these neuroimaging findings result from downstream effects of phasic dopamine firing in subcortical areas (Arnold et al, 2015).…”