Ventral Striatal Dopamine Modulation of Different Forms of Behavioral Flexibility

Different forms of behavioral flexibility are facilitated by interactions between separate regions of the prefrontal cortex and their striatal outputs. However, the contribution of ventral striatal dopamine (DA) to these functions is unclear. The present study assessed the involvement of DA receptors in the nucleus accumbens (NAc) core on either between- or within-strategy shifts using operant chamber-based tasks. Strategy set-shifting required rats initially to learn a visual-cue discrimination and, on the following day, shift to using an egocentric spatial response strategy to obtain reward. For reversal learning, rats were initially trained on a response discrimination and then required to select the opposite lever to receive food reward. Intra-NAc microinfusions of D-1 (SCH23390) but not D-2 (eticlopride) receptor antagonists impaired set-shifting, disrupting the maintenance of a new strategy. Conversely, supranormal activation of D-2 (quinpirole) but not D-1 (SKF81297) receptors also impaired set-shifting, inducing perseverative deficits. However, only infusions of the D-2 agonist impaired reversal learning, but did so without disrupting initial response learning. Thus, mesoaccumbens DA, acting on D-1 receptors, selectively facilitates complex forms of flexibility requiring shifts between different strategies, but does not appear to contribute to simpler forms of flexibility entailing shifts of specific stimulus-reward associations. In contrast, abnormal increases in D-2 receptor activity cause a more general impairment in behavioral flexibility. These findings suggest that deficits in these forms of executive functioning observed in disorders linked to dysfunction of the DA system may be attributable in part to aberrant increases or decreases in mesoaccumbens DA activity. Neuropsychopharmacology (2009) 34, 2041-2052; doi: 10.1038/npp.2009.21; published online 4 March 2009