There is increasing evidence that the left lateral frontal cortex is hierarchically organized such that higher-order regions have an asymmetric top–down influence over lower order regions. However, questions remain about the underlying neuroarchitecture of this hierarchical control organization. Within the frontal cortex, dopamine plays an important role in cognitive control functions, and we hypothesized that dopamine may preferentially influence top–down connections within the lateral frontal hierarchy. Using a randomized, double-blind, within-subject design, we analyzed resting-state fMRI data of 66 healthy young participants who were scanned once each after administration of bromocriptine (a dopamine agonist with preferential affinity for D2 receptor), tolcapone (an inhibitor of catechol-O-methyltransferase), and placebo, to determine whether dopaminergic stimulation modulated effective functional connectivity between hierarchically organized frontal regions in the left hemisphere. We found that dopaminergic drugs modulated connections from the caudal middle frontal gyrus and the inferior frontal sulcus to both rostral and caudal frontal areas. In dorsal frontal regions, effectivity connectivity strength was increased, whereas in ventral frontal regions, effective connectivity strength was decreased. These findings suggest that connections within frontal cortex are differentially modulated by dopamine, which may bias the influence that frontal regions exert over each other.

Dopamine (DA) has been implicated in modulating multiple cognitive control processes, including the robust maintenance of task sets and memoranda in the face of distractors (cognitive stability) and, conversely, the ability to switch task sets or update the contents of working memory when it is advantageous to do so (cognitive flexibility). In humans, the limited specificity of available pharmacological probes has posed a challenge for understanding the mechanisms by which DA, acting on multiple receptor families across the PFC and striatum, differentially influences these cognitive processes. Using a within-subject, placebo-controlled design, we contrasted the impact of two mechanistically distinct DA drugs, tolcapone (an inhibitor of catechol- O -methyltransferase [COMT], a catecholamine inactivator) and bromocriptine (a DA agonist with preferential affinity for the D2 receptor), on the maintenance and switching of task rules. Given previous work demonstrating that drug effects on behavior are dependent on baseline DA tone, participants were stratified according to genetic polymorphisms associated with cortical (COMT Val158Met) and striatal (Taq1A) DA system function. Our results were partially consistent with an inverted-U-shaped relationship between tolcapone and robust rule maintenance (interaction with COMT genotype) and between bromocriptine and cued rule switching (interaction with Taq1A genotype). However, when task instructions were ambiguous, a third relationship emerged to explain drug effects on spontaneous task switching (interaction of COMT genotype and bromocriptine). Together, this pattern of results suggests that the effects of DA drugs vary not only as a function of the DA system component upon which they act but also on subtle differences in task demands and context.