Prefrontal dopamine and behavioral flexibility: shifting from an "inverted-U" toward a family of functions.

Studies on prefrontal cortex (PFC) dopamine (DA) function have revealed its essential role in mediating a variety of cognitive and executive functions. A general principle that has emerged (primarily from studies on working memory) is that PFC DA, acting on D1 receptors, regulates cognition in accordance to an "inverted-U" shaped function, so that too little or too much activity has detrimental effects on performance. However, contemporary studies have indicated that the receptor mechanisms through which mesocortical DA regulates different aspects of behavioral flexibility can vary considerably across different DA receptors and cognitive operations. This article will review psychopharmacological and neurochemical data comparing and contrasting the cognitive effects of antagonism and stimulation of different DA receptors in the medial PFC. Thus, set-shifting is dependent on a co-operative interaction between PFC D1 and D2 receptors, yet, supranormal stimulation of these receptors does not appear to have detrimental effects on this function. On the other hand, modification of cost/benefit decision biases in situations involving reward uncertainty is regulated in complex and sometimes opposing ways by PFC D1 vs. D2 receptors. When viewed collectively, these findings suggest that the "inverted-U" shaped dose-response curve underlying D1 receptor modulation of working memory is not a one-size-fits-all function. Rather, it appears that mesocortical DA exerts its effects via a family of functions, wherein reduced or excessive DA activity can have a variety of effects across different cognitive domains.