Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor (DRD2) in flexible behavioral adaptation, mostly shown in reward-based learning paradigms. Recent evidence from imaging genetics indicates that also intentional cognitive flexibility, associated with lateral frontal cortex, is affected by variations in DRD2 signaling. In the present functional MRI study, we tested the effects of a direct pharmacological manipulation of DRD2 stimulation on intentional flexibility in a task-switching context, requiring switches between cognitive task rules and between response hands. In a double-blind, counterbalanced design, participants received either a low dose of the DRD2 agonist bromocriptine or a placebo in two separate sessions. Bromocriptine modulated BOLD signal during rule switching: rule-switching-related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo, at comparable performance levels. Fronto-striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions. Hand-switching-related activity, in contrast, was reduced under bromocriptine in sensori-motor regions. Our results provide converging evidence for an involvement of DRD2 signaling in fronto-striatal mechanisms underlying intentional flexibility, and indicate that the neural mechanisms underlying different types of flexibility (cognitive vs. motor) are affected differently by increased dopaminergic stimulation.

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