Occupancy of Dopamine D₃ and D₂ Receptors by Buspirone: A [¹¹C]-(+)-PHNO PET Study in Humans

There is considerable interest in blocking the dopamine D₃ receptor (DRD₃) versus the D₂ receptor (DRD₂) to treat drug addiction. However, there are currently no selective DRD₃ antagonists available in the clinic. The anxiolytic drug buspirone has been proposed as a potential strategy as findings suggest that this drug has high in vitro affinity for DRD₃, binds to DRD₃ in brain of living non-human primate, and also disrupts psychostimulant self-administration in preclinical models. No study has explored the occupancy of DRD₃ by buspirone in humans. Here, we used positron emission tomography (PET) and the D₃ -preferring probe, [¹¹C]-(+)-PHNO, to test the hypothesis that buspirone will occupy (decreases [¹¹C]-(+)-PHNO binding) the DRD₃ more readily than the DRD₂. Eight healthy participants underwent [¹¹C]-(+)-PHNO scans after single oral dose administration of placebo and 30, 60, and 120 mg of buspirone in a single-blind within-subjects design. [¹¹C]-(+)-PHNO binding in DRD₂- and DRD₃-rich areas was decreased by the highest (60-120 mg), but not the lowest (30 mg), doses of buspirone. The maximal occupancy obtained was ∼25% in both areas. Plasma levels of prolactin (a DRD₂ marker) correlated with percentage occupancy after orally administered buspirone. Self-reported dizziness and drowsiness increased after buspirone but that did not correlate with receptor occupancy in any region. Overall, the modest occupancy of DRD₂ and DRD₃ even at high acute doses of buspirone, yielding high levels of metabolites, suggests that buspirone may not be a good drug to preferentially block DRD₃ in humans.