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• W1973313963 abstract "Long-term occupancy of dopamine D2-receptors, as achieved by chronic treatment with antipsychotics, leads to D2-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 D2-receptor blockade (duration and percentage of blockade) that lead to upregulation. In this study, we investigated the effects of different degrees (60 vs >80%) and durations (a transient peak vs 24 h/day) of D2-receptor blockade on inducing this upregulation. These different patterns of D2-receptor occupancy kinetics were produced in cats using bolus vs constant infusion of haloperidol for 4 weeks. D2-receptors were measured using positron emission tomography and Scatchard analyses of [11C]raclopride binding, before and after withdrawal of treatment. Continuously high (80% for 24 h/day) D2-receptor blockade led to a robust upregulation of striatal D2-receptors that was maximal at 1-week withdrawal (35±5%) and still detectable at 2-week withdrawal (20±3%). This pattern of D2-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) D2-receptor blockade did not produce any of these effects. The long-term effect of haloperidol on D2-receptor density and behavioral tolerance thus appears to be dependent not only on a critical threshold of D2-receptor blockade but also on the daily duration of D2-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." @default.
• W1973313963 created "2016-06-24" @default.
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• W1973313963 date "2008-08-06" @default.
• W1973313963 modified "2023-10-11" @default.
• W1973313963 title "D2-Receptor Upregulation is Dependent upon Temporal Course of D2-Occupancy: A Longitudinal [11C]-Raclopride PET Study in Cats" @default.
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• W1973313963 doi "https://doi.org/10.1038/npp.2008.116" @default.
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