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Long-term occupancy of dopamine D(2)-receptors, as achieved by chronic treatment with antipsychotics, leads to D(2)-receptor upregulation, and this upregulation is thought to be responsible for loss of efficacy and development of tardive dyskinesia. However, little is known about the parameters of D(2)-receptor blockade (duration and percentage of blockade) that lead to upregulation. In this study, we investigated the effects of different degrees (60 vs &gt;80%) and durations (a transient peak vs 24 h/day) of D(2)-receptor blockade on inducing this upregulation. These different patterns of D(2)-receptor occupancy kinetics were produced in cats using bolus vs constant infusion of haloperidol for 4 weeks. D(2)-receptors were measured using positron emission tomography and Scatchard analyses of [(11)C]raclopride binding, before and after withdrawal of treatment. Continuously high (80% for 24 h/day) D(2)-receptor blockade led to a robust upregulation of striatal D(2)-receptors that was maximal at 1-week withdrawal (35+/-5%) and still detectable at 2-week withdrawal (20+/-3%). This pattern of D(2)-receptor blockade also induced behavioral tolerance to the effect of haloperidol on spontaneous locomotor activity. Continuously moderate (60% for 24 h/day) or transiently high (80% for a few hours/day) D(2)-receptor blockade did not produce any of these effects. The long-term effect of haloperidol on D(2)-receptor density and behavioral tolerance thus appears to be dependent not only on a critical threshold of D(2)-receptor blockade but also on the daily duration of D(2)-receptors blockade. This suggests that as far as antipsychotics are concerned, not only dose but disbursment throughout the day have an impact on eventual pharmacodynamic and behavioral outcomes.

D2-Receptor Upregulation is Dependent upon Temporal Course of D2-Occupancy: A Longitudinal [11C]-Raclopride PET Study in Cats