Rationale: Dopamine is strongly implicated in the ability to shift behavior in response to changing stimulus-reward contingencies.

Objectives: We investigated the effects of systemic administration of the D2/D3 receptor agonist quinpirole (0.1, 0.3 mg/kg), the D2/D3 receptor antagonist raclopride (0.1, 0.3 mg/kg), the selective D3 antagonist nafadotride (0.3, 1.0 mg/kg), and combined administration of raclopride (0.1 mg/kg) or nafadotride (1.0 mg/kg) with quinpirole (0.3 mg/kg) on spatial discrimination and reversal learning.

Materials and methods: Rats were trained on an instrumental two-lever spatial discrimination and reversal learning task. Both levers were presented, only one of which was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, a reversal was introduced.

Results: None of the drugs altered performance during retention of the previously reinforced contingencies. Quinpirole (0.3 mg/kg) significantly impaired reversal learning by increasing both trials and incorrect responses to criterion in reversal phase, a pattern of behavior manifested as increased perseverative responding on the previously reinforced lever. In contrast, neither raclopride nor nafadotride when administered alone altered reversal performance. However, raclopride blocked the quinpirole-induced reversal deficit, whereas combined administration of nafadotride and quinpirole affected not only performance during the reversal but also the retention phase. The reversal impairment resulting from co-administration of nafadotride and quinpirole was associated with both perseverative and learning errors.

Conclusions: Our data indicate distinct roles for D2 and D3 receptors in the capacity to modify behavior flexibly in the face of environmental change.