COMT and ANKK1 gene-gene interaction modulates contextual updating of mental representations.

The differential expression of the dopamine transmitter through its prefrontostriatal pathway has been proposed to account for individual differences in the updating of higher order task representations. Here we examined the interaction between two polymorphic variations of genes involved in the regulation of prefrontal and striatal dopamine (catechol-O-methyltransferase-COMT and ANKK1) on the neural mechanisms of task-set switching. A task-cueing paradigm was employed to measure behavioral costs and a scalp-recorded specific brain potential (novelty-P3) associated to distinct context updating operations in the face of either sensory or task novelty. The interaction between the COMT and ANKK1 genes was evidenced by corresponding specific behavioral costs and novelty-P3 amplitude enhancements reflecting task-set updating mechanisms. This effect was found only in individuals combining genes that yielded a balance between dopamine concentrations and receptor densities. Individuals displaying a putative "unbalance" showed enhanced novelty-P3 responses to all sensory changes, indicative of a task-set updating to sensory cues in a task-context independent fashion. These results support the epistasis of COMT and ANKK1 phenotypes in the flexible control of contextual information in humans.