Dopamine D₃ receptor availability is associated with inflexible decision making

Dopamine D_2/3 receptor signaling is critical for flexible adaptive behavior; however, it is unclear whether D₂, D₃, or both receptor subtypes modulate precise signals of feedback and reward history that underlie optimal decision making. Here, PET with the radioligand [¹¹C]-(+)-PHNO was used to quantify individual differences in putative D₃ receptor availability in rodents trained on a novel threechoice spatial acquisition and reversal-learning task with probabilistic reinforcement. Binding of [¹¹C]-(+)-PHNO in the midbrain was negatively related to the ability of rats to adapt to changes in rewarded locations, but not to the initial learning. Computational modeling of choice behavior in the reversal phase indicated that [¹¹C]-(+)-PHNO binding in the midbrain was related to the learning rate and sensitivity to positive, but not negative, feedback. Administration of a D₃-preferring agonist likewise impaired reversal performance by reducing the learning rate and sensitivity to positive feedback. These results demonstrate a previously unrecognized role for D₃ receptors in select aspects of reinforcement learning and suggest that individual variation in midbrain D₃ receptors influences flexible behavior. Our combined neuroimaging, behavioral, pharmacological, and computational approach implicates the dopamine D₃ receptor in decision-making processes that are altered in psychiatric disorders.