Potential role of dopamine transporter in behavioral flexibility.

Behavioral flexibility is subserved by the prefrontal cortex and the basal ganglia. Orbitofrontal cortex (OFC) and dorsomedial striatum (DMS) form a functional frontocorticostriatal circuit crucial for the mediation of flexibility during reversal learning via dopamine (DA) neurotransmission. The regulatory control in maintaining DA homeostasis and function is provided by the dopamine transporter (DAT), which therefore likely plays a significant role in controlling the influence of DA on cognitive processes. Here we used a gene knockout mouse model to investigate the role of DAT in the performance on the Attentional Set-Shifting Task (ASST) stages dependent upon the OFC and the DMS. Additionally, behavior of mice after repeated administration of selective DAT inhibitor, GBR 12909, was examined. The animals were treated with the inhibitor to elicit a compensatory DAT up-regulation following withdrawal. Learning was slower and the number of errors during reversal learning and intra-dimensional shift stages was higher in DAT+/- mutant mice than in WT mice. GBR 12909-treated mice had deficits in reversal stages of the ASST. Neuronal activation in the OFC and DMS during the ASST was examined with early growth response proteins 1 and 2 (egr-1, egr-2) immunohistochemistry. Density of egr-2 labeled cells in the OFC was lower in mutant mice than in wild-types during reversal learning and the expression of the egr-1 was lower in mutant mice in the OFC and DMS during reversal and intra-dimensional shift stages. Mice with decreased DAT levels displayed behavioral difficulties that were accompanied by a lower task-induced activation of neurons in brain regions involved in the reversal learning. Altogether, these data indicate the role of the DAT in the behavioral flexibility.