Genetically determined interaction between the dopamine transporter and the D₂ receptor on prefronto-striatal activity and volume in humans

Dopamine modulation of neuronal activity during memory tasks identifies a nonlinear inverted-U shaped function. Both the dopamine transporter (DAT) and dopamine D₂ receptors (encoded by DRD₂) critically regulate dopamine signaling in the striatum and in prefrontal cortex during memory. Moreover, in vitro studies have demonstrated that DAT and D₂ proteins reciprocally regulate each other presynaptically. Therefore, we have evaluated the genetic interaction between a DRD₂ polymorphism (rs1076560) causing reduced presynaptic D₂ receptor expression and the DAT 3′-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 significant DRD₂/DAT interaction in prefrontal cortex and striatum BOLD activity during both working memory and encoding of recognition memory. The differential effect on BOLD activity of the DAT variant was mostly manifest in the context of the DRD₂ allele 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 D₂ knock-out animals (D2R^-/-) indicate that DAT and D₂ proteins interact in vivo. Together, our results demonstrate that the interaction between genetic variants in DRD₂ and DAT critically modulates the nonlinear relationship between dopamine and neuronal activity during memory processing.