Dopamine (DA) input to the prefrontal cortex (PFC), acting on D1 receptors, plays an essential role in mediating working memory functions. In comparison, less is known about the importance of distinct PFC DA receptor subtypes in mediating executive functions such as set-shifting. The present study assessed the effects of microinfusion of D2 and D4 receptor antagonists, and D1, D2, and D4 receptor agonists into the PFC on performance of a maze-based set-shifting task. In Experiment 1, rats were trained on a response discrimination task, and then on a visual-cue discrimination task requiring rats to suppress the use of the response strategy and approach the previously irrelevant cue to locate food. In Experiment 2, the order of training was reversed. Infusions of the D2 antagonist eticlopride, or the D4 agonist PD-168,077, impaired shifting from a response to a visual-cue discrimination strategy and vice versa, and caused a selective increase in perseverative errors. In contrast, infusions of the D4 antagonist L-745,870 improved set-shifting. Infusions of the D1 agonist SKF81297 or the D2 agonist quinpirole caused no reliable effect. These data, in combination with previous reports of impaired setshifting following D1 receptor blockade, suggest that multiple receptors in the PFC are essential for set-shifting and that the mechanisms by which PFC DA mediates behavioral flexibility may be different from those underlying working memory. These findings may have important implications for developing novel treatments for cognitive deficits observed in disorders such as attentional deficit and hyperactivity disorder and schizophrenia.

The ability to behave in a flexible manner is an executive function mediated in part by different regions of the prefrontal cortex. The present study investigated the role of two major efferents of the prefrontal cortex, the nucleus accumbens (NAc) core and shell, in behavioral flexibility using a maze-based strategy set-shifting task. During initial discrimination training, rats learned to use either an egocentric response or a visual-cue discrimination strategy to obtain food reward. During the set shift, animals had to shift from the previously acquired response or visual-cue-based strategy and learn the alternate discrimination. Inactivation of the NAc core, induced by infusion of the GABA agonists baclofen and muscimol, did not impair initial acquisition of either a response or visual-cue discrimination but severely disrupted shifting from one strategy to another. Analysis of the type of errors revealed that impairments in set shifting were not attributable to increased perseveration but to a disruption of the acquisition and maintenance of a new strategy. In contrast, inactivation of the NAc shell did not impair acquisition of either a response or a visual-cue discrimination, or shifting from one strategy to another. However, inactivation of the NAc shell before initial discrimination training improved performance during the set shift relative to control animals. These data indicate that the NAc core and shell make dissociable contributions to behavioral flexibility during set shifting. The NAc core facilitates the acquisition and maintenance of novel behavioral strategies and elimination of inappropriate response options, whereas the shell may mediate learning about irrelevant stimuli.

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