Converging evidence supports a role for mesocorticolimbic dopaminergic systems in a subject's ability to shift behavior in response to changing stimulus-reward contingencies. To characterize the dopaminergic mechanisms involved in this function, we quantified the effects of subtype-specific dopamine (DA) receptor antagonists on acquisition, retention, and reversal of a visual discrimination task in non-human primates (Chlorocebus aethiops sabaeus). We used a modified Wisconsin General Test Apparatus that was equipped with three food boxes, each fitted with a lid bearing a unique visual cue; one of the cues concealed a food reward, whereas the other two concealed an empty box. The monkeys were trained first to acquire a novel discrimination (eg A(+), B-, C-) in a single session, before experiencing either a reversal of the discrimination (eg A(-), B+,C-) or the acquisition of a completely new discrimination (eg D+, E-, F-), on the following day. Systemic administration of the D-2/D-3 receptor antagonist raclopride (0.001 -0.03 mg/kg) failed to significantly affect the performance of reversal learning when reversal sessions were run without a retention session. But, raclopride (0.03 mg/ kg) significantly impaired performance under the reversal condition when reversal sessions were run right after a retention session; however, it did not affect acquisition of a novel visual discrimination. Specifically, raclopride significantly increased the number of reversal errors made before reaching the performance criterion in the reversal, but not in new learning sessions. In contrast, the D-1/D-5 receptor antagonist SCH 23390 did not significantly modulate acquisition of a novel discrimination or reversal learning at doses (0.001 -0.03 mg/kg, i.m.) that did not suppress behavior generally. In addition, none of the drug treatments affected retention of a previously learned discrimination. The results strongly suggest that D-2/D-3 receptors, but not D-1/D-5 receptors, selectively mediate reversal learning, without affecting the capacity to learn a new stimulus-reward association. These data support the hypothesis that phasic DA release, acting through D-2-like receptors, mediates behavioral flexibility.
