title: D2-receptor upregulation is dependent upon temporal course of D2-occupancy: a longitudinal [11C]-raclopride PET study in cats.
abstract: 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 >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.
authors.affiliation: The Vivian Rakoff Positron Emission Tomography Unit, Centre for Addiction and Mental Health and University of Toronto, Toronto, ON, Canada. nathalie.ginovart@medecine.unige.ch
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ginovart
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.forename: Doug
authors.initials: D
authors.lastname: Hussey
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
mesh_terms: D000818:Animals; D002415:Cats; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D008137:Longitudinal Studies; D009043:Motor Activity / Q000187:drug effects; D049268:Positron-Emission Tomography; D020891:Raclopride / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D020891:Raclopride; D006220:Haloperidol