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'-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=0.40), in line with meta-analyses, 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.

Figure 1

Clusters showing an interaction between Genotype (9R, 10/10) and Drug (methylphenidate, placebo) in the contrast correct no-go>correct odd (family-wise error corrected (FWEc), peak voxel threshold P<0.001, uncorrected). Slices in neurologic convention (right side=right side).

Figure 2

The interaction between Genotype (9R, 10/10) and Drug (placebo (PLC), methylphenidate (MPH)) in each of the clusters in the contrast correct no-go>correct odd (see Table 2). The y axis describes mean BOLD signal activation in the corresponding cluster. Error bars represent the SEM.