¹The Vivian Rakoff Positron Emission Tomography Unit, Centre for Addiction and Mental Health and University of Toronto, Toronto, ON, Canada

Correspondence: Dr N Ginovart, Neuroimaging Unit, University Department of Psychiatry, University of Geneva, Chemin du Petit Bel-Air, 2, Geneva CH-1225, Switzerland. Tel: +41 22 305 5391; Fax: +41 22 305 5375; E-mail: nathalie.ginovart@medecine.unige.ch

Received 28 January 2008; Revised 28 June 2008; Accepted 29 June 2008; Published online 6 August 2008.

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 (355%) and still detectable at 2-week withdrawal (203%). 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.