Mesocortical dopamine modulation of executive functions: beyond working memory

Rationale: Dopamine (DA) neurotransmission in the prefrontal cortex (PFC) is known to play an essential role in mediating executive functions such as the working memory. DA exerts these effects by acting on D-1 receptors because blockade or stimulation of these receptors in the PFC can impair performance on delayed response tasks. However, comparatively less is known about dopaminergic mechanisms that mediate other executive functions regulated by the PFC. Furthermore, the functional importance of other DA receptor subtypes that reside on PFC neurons (D-2 and D-4) is unclear. Objectives: This review will summarize previous findings and previously unpublished data addressing the contribution of PFC DA to higher-order cognition. We will compare the DA receptor mechanisms, which regulate executive functions such as working memory, behavioral flexibility, and decision-making. Results and conclusions: Whereas PFC D-1 receptor activity is of primary importance in working memory, D-1 and D-2 receptors act in a cooperative manner to facilitate behavioral flexibility. We note that the principle of the "inverted U-shaped" function of D-1 receptor activity mediating working memory does not necessarily apply to other PFC functions. DA in different subregions of the PFC also mediates decision-making assessed with delay discounting or effort-based procedures, and we report that D-1, D-2, and D-4 receptors in the medial PFC contribute to decision-making when animals must bias the direction of behavior to avoid aversive stimuli, assessed with a conditioned punishment procedure. Thus, mesocortical DA modulation of distinct executive functions is subserved by dissociable profiles of DA receptor activity in the PFC.