Acutely administered antipsychotic drugs are highly selective for dopamine D2 over D3 receptors

We showed previously, using [(3)H]-(+)-4-propyl-9-hydroxynaphthoxazine ([(3)H]-(+)-PHNO) autoradiography, that several antipsychotic drugs do not occupy dopamine D3 receptors at clinically-relevant doses in rat. This is an unexpected finding considering the near-equivalent in vitro affinity of these drugs for D2 and D3 receptors. The purpose of the current study was to address two possible methodological limitations of our previous report, namely that (1) [(3)H]-(+)-PHNO may have been administered at non-tracer dose, potentially causing underestimate of D3 receptor occupancy, and (2) antipsychotic drugs were administered chronically, potentially causing increased D3 receptor expression not accounted for in the vehicle-treated control group. We found that decreasing [(3)H]-(+)-PHNO dose from 5.6nmol/kg (our previous dose) to 0.6nmol/kg caused a >60% increase in [(3)H]-(+)-PHNO binding to D3 receptors in cerebellar lobes 9 and 10, indicating that our previous study was indeed conducted under non-tracer dose conditions. However, neither reducing [(3)H]-(+)-PHNO dose further to 0.3nmol/kg (a tracer dose), nor administering antipsychotics acutely affected antipsychotic receptor occupancy. At clinically-relevant levels of D2 occupancy (57-82% inhibition of striatal binding), neither olanzapine nor haloperidol occupied D3 receptors, while clozapine occupied D3 receptors at levels similar to our previous report (33%). Risperidone moderately occupied D3 receptors (40%), but at a dose occupying >90% of D2 receptors and therefore of questionable clinical relevance. These findings demonstrate that the lack of antipsychotic occupancy of D3 receptors is not attributable to limitations of our previous study. These results suggest that D3 receptor blockade is not necessary for the therapeutic effects of the antipsychotic drugs examined.