Genetically Determined Interaction between the Dopamine Transporter and the D2Receptor on Prefronto-Striatal Activity and Volume in Humans

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Abstract
Dopamine modulation of neuronal activity during memory tasks identifies a nonlinear inverted-U shaped function. Both the dopamine transporter (DAT) and dopamine D2receptors (encoded byDRD2) critically regulate dopamine signaling in the striatum and in prefrontal cortex during memory. Moreover,in vitrostudies have demonstrated that DAT and D2proteins reciprocally regulate each other presynaptically. Therefore, we have evaluated the genetic interaction between aDRD2polymorphism (rs1076560) causing reduced presynaptic D2receptor expression and theDAT3′-VNTR variant (affecting DAT expression) in a large sample of healthy subjects undergoing blood oxygenation level-dependent (BOLD)-functional magnetic resonance imaging (MRI) during memory tasks and structural MRI. Results indicated a significantDRD2/DATinteraction in prefrontal cortex and striatum BOLD activity during both working memory and encoding of recognition memory. The differential effect on BOLD activity of theDATvariant was mostly manifest in the context of theDRD2allele associated with lower presynaptic expression. Similar results were also evident for gray matter volume in caudate. These interactions describe a nonlinear relationship between compound genotypes and brain activity or gray matter volume. Complementary data from striatal protein extracts from wild-type and D2knock-out animals (D2R−/−) indicate that DAT and D2proteins interactin vivo. Together, our results demonstrate that the interaction between genetic variants inDRD2andDATcritically modulates the nonlinear relationship between dopamine and neuronal activity during memory processing.