Increased dopamine D 2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study

Silvestri, S.; Seeman, Mary V.; Negrete, J.C.; Houle, Sylvain; Shammi, Chekkera; Remington, G.; Kapur, Shitij; Zipursky, Robert B.; Wilson, Alan A.; Christensen, Bruce K.; Seeman, Philip

doi:10.1007/s002130000532

Cited by 273 publications

(165 citation statements)

References 48 publications

Supporting

Mentioning

153

Contrasting

Unclassified

Order By: Relevance

“…This pattern of D 2 -receptor blockade produced a robust upregulation of striatal D 2 -receptors and induced the development of behavioral tolerance to the effect of haloperidol on spontaneous locomotor activity. These consequences are similar to those reported in patients on haloperidol medication, in whom stable haloperidol plasma concentrations and high levels of D 2 -receptor occupancies are maintained, and who show D 2 -upregulation in the striatum (Lee et al, 1978;Mita et al, 1986;Silvestri et al, 2000). Although this continuous pattern of high D 2 -receptor blockade produced the undesirable effects of the drug, continuous but only moderate (B60% throughout the day) levels of D 2 -receptor blockade did not produce any of these effects.…”

Section: Discussionsupporting

confidence: 81%

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

Ginovart

Wilson

Hussey

et al. 2008

Neuropsychopharmacol

Self Cite

View full text Add to dashboard Cite

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 480%) 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.

show abstract

Section: Discussionsupporting

confidence: 81%

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

Ginovart

Wilson

Hussey

et al. 2008

Neuropsychopharmacol

Self Cite

View full text Add to dashboard Cite

show abstract

“…This was confirmed by another study, which did find a higher D2 receptor density in patients with schizophrenia after intake of antipsychotics. [34][35][36] DRD2 Ser311Cys and À141C Ins/Del. The Ser311Cys polymorphism is an effective cAMP inhibitor in DRD2 leading to activation of intracellular signalling.…”

Section: Methodsmentioning

confidence: 99%

Antipsychotic-induced tardive dyskinesia and polymorphic variations in COMT, DRD2, CYP1A2 and MnSOD genes: a meta-analysis of pharmacogenetic interactions

Bakker¹,

Harten²,

2008

Mol Psychiatry

138

118

View full text Add to dashboard Cite

Despite accumulating evidence pointing to a genetic basis for tardive dyskinesia, results to date have been inconsistent owing to limited statistical power and limitations in molecular genetic methodology. A Medline, EMBASE and PsychINFO search for literature published between 1976 and June 2007 was performed, yielding 20 studies from which data were extracted for calculation of pooled estimates using meta-analytic techniques. Evidence from pooled data for genetic association with tardive dyskinesia (TD) showed (1) in COMT val158met , using Val-Val homozygotes as reference category, a protective effect for Val-Met heterozygotes (OR = 0.63, 95% CI: 0.46-0.86, P = 0.004) and Met carriers (OR = 0.66, 95% CI: 0.49-0.88, P = 0.005); (2) in Taq1A in DRD2, using the A1 variant as reference category, a risk-increasing effect for the A2 variant (OR = 1.30, 95% CI: 1.03-1.65, P = 0.026), and A2-A2 homozygotes using A1-A1 as reference category (OR = 1.80, 95% CI: 1.03-3.15, P = 0.037); (3) in MnSOD Ala9Val, using Ala-Ala homozygotes as reference category, a protective effect for Ala-Val (OR = 0.37, 95% CI: 0.17-0.79, P = 0.009) and for Val carriers (OR = 0.49, 95% CI: 0.24-1.00, P = 0.047). These analyses suggest multiple genetic influences on TD, indicative of pharmacogenetic interactions. Although associations are small, the effects underlying them may be subject to interactions with other loci that, when identified, may have acceptable predictive power. Future genetic research will take advantage of new genomic knowledge.

show abstract

“…Indeed, chronic exposure to haloperidol upregulates D 2 -dopaminergic receptors and downregulates D 1 receptors inducing cognitive dysfunctions (Lidow and GoldmanRakic, 1994;Castner et al, 2000;Silvestri et al, 2000). In our protocol, a minimum washout period of 10 d was observed between two consecutive drug challenges.…”

Section: Methodsmentioning

confidence: 99%

Frontal Feedback-Related Potentials in Nonhuman Primates: Modulation during Learning and under Haloperidol

Vezoli

Procyk²

2009

J. Neurosci.

View full text Add to dashboard Cite

Feedback monitoring and adaptation of performance involve a medial reward system including medial frontal cortical areas, the medial striatum, and the dopaminergic system. A considerable amount of data has been obtained on frontal surface feedback-related potentials (FRPs) in humans and on the correlate of outcome monitoring with single unit activity in monkeys. However, work is needed to bridge knowledge obtained in the two species. The present work describes FRPs in monkeys, using chronic recordings, during a trial and error task. We show that frontal FRPs are differentially sensitive to successes and failures and can be observed over long-term periods. In addition, using the dopamine antagonist haloperidol we observe a selective effect on FRP amplitude that is absent for pure sensoryrelated potentials. These results describe frontal dopaminergic-dependent FRPs in monkeys and corroborate a human-monkey homology for performance monitoring signals.

show abstract

Increased dopamine D 2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study

Cited by 273 publications

References 48 publications

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

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

Antipsychotic-induced tardive dyskinesia and polymorphic variations in COMT, DRD2, CYP1A2 and MnSOD genes: a meta-analysis of pharmacogenetic interactions

Frontal Feedback-Related Potentials in Nonhuman Primates: Modulation during Learning and under Haloperidol

Contact Info

Product

Resources

About