In vivo occupancy of striatal and temporal cortical D2/D3 dopamine receptors by typical antipsychotic drugs

1999 ◽  
Vol 175 (3) ◽  
pp. 231-238 ◽  
Author(s):  
Valeria Bigliani ◽  
Rachel S. Mulligan ◽  
Paul D. Acton ◽  
Dimitris Visvikis ◽  
Peter J. Ell ◽  
...  
Keyword(s):  
Dopamine Receptors ◽  
Antipsychotic Drugs ◽  
Specific Binding ◽  
Temporal Cortex ◽  
Receptor Occupancy ◽  
Typical Antipsychotic ◽  
Dopamine Hypothesis ◽  
Antipsychotic Drug Treatment ◽  
The Relationship

BackgroundThe dopamine hypothesis proposes that antipsychotic drugs act primarily through limbic cortical D2/D2-like dopamine receptor blockade.AimTo evaluate this hypothesis with the D2/D3-selective SPET probe [123I]-epidepride.Method[123I]-epidepride SPETscans were performed on 12 patients with schizophrenia treated with antipsychotics and 11 age-matched healthy controls. [123I]-epidepride specific binding to D2/D3 dopamine receptors was estimated, and relative percentage D2/D3 receptor occupancy by typical antipsychotic drugs determined.ResultsMean (s.d.) daily dose was 669.12 (516.8) mg chlorpromazine equivalents. Mean percentage D2/D3 receptor occupancy was 81.6 (8.1) and 73.2 (13.9) in the temporal cortex and striatum respectively.ConclusionsTypical antipsychotic drug treatment is associated with substantial temporal cortical D2/D3 receptor occupancy. The relationship between this and efficacy is poor in patients with treatment-resistant schizophrenia.

scholarly journals Striatal and extra-striatal D2/D3 dopamine receptor occupancy by quetiapine in vivo

2000 ◽  
Vol 177 (5) ◽  
pp. 408-415 ◽  
Author(s):  
C. M. E. Stephenson ◽  
V. Bigliani ◽  
H. M. Jones ◽  
R. S. Mulligan ◽  
P. D. Acton ◽  
...  
Keyword(s):  
Single Photon ◽  
Specific Binding ◽  
Photon Emission ◽  
Temporal Cortex ◽  
Receptor Occupancy ◽  
Typical Antipsychotic ◽  
Relative Percentage ◽  
Daily Dose ◽  
Cortical Regions

BackgroundSelective action at limbic cortical dopamine D2-like receptors could mediate atypical antipsychotic efficacy with few extrapyramidal side-effects.AimsTo test the hypothesis that quetiapine has ‘limbic selective’ D2/D3 receptor occupancy in vivo.MethodThe high-affinity D2/D3 ligand [123I]-epidepride and single photon emission tomography were used to estimate D2/D3 specific binding and an index of relative percentage D2/D3 occupancy in striatal and temporal cortical regions for quetiapine-treated patients (n=6). Quetiapine-, and previously studied typical-antipsychotic- and clozapine-treated patients were compared.ResultsMean (s.d.) relative percentage D2/D3 receptor occupancy by quetiapine was 32.0% (14.6) in striatum and 60.1% (17.2) in temporal cortex (mean daily dose 450 mg: range 300–700 mg/day). Quetiapine treatment resulted in limbic selective D2/D3 blockade similar to clozapine and significantly higher than typical antipsychotics.ConclusionsPreliminary data suggest that limbic selective D2/D3 receptor blockade is important for atypical drug action.

The Importance of Serotonin-Dopamine Interactions in the Action of Clozapine

1992 ◽  
Vol 160 (S17) ◽  
pp. 22-29 ◽  
Author(s):  
Herbert Y. Meltzer
Keyword(s):  
Atypical Antipsychotic ◽  
Atypical Antipsychotics ◽  
Antipsychotic Drugs ◽  
Typical Antipsychotic ◽  
Atypical Antipsychotic Drugs ◽  
Clinical Dose ◽  
High Affinity ◽  
The Relationship

Clozapine has an affinity for the dopamine (DA) D2 receptor which is relatively weak but is in line with its average clinical dose when compared with typical neuroleptic drugs. A few atypical antipsychotic drugs may have high absolute affinities for the D2 receptor, but most are weak D2 blockers. The atypical antipsychotic drugs also differ from the typical antipsychotic drugs by a relatively high affinity for the serotonin (5-HT2) receptor. This is evident on both in vitro and in vivo binding to cortical 5-HT2 receptors. The atypical antipsychotics are best distinguished from the typical antipsychotics on the basis of the relationship between strong 5-HT2 and weak D2 affinities. High D1 receptor binding is not characteristic of the group of atypical drugs. A new group of putative atypical antipsychotic drugs with high affinities for 5-HT2 compared to D2 receptors is under study.

Mechanisms of Action of Atypical Antipsychotics

CNS Spectrums ◽  
2005 ◽  
Vol 10 (S10) ◽  
pp. 5-11 ◽  
Author(s):  
Fernando Cañas
Keyword(s):  
Clinical Utility ◽  
Atypical Antipsychotics ◽  
Antipsychotic Drugs ◽  
Receptor Occupancy ◽  
Conventional Antipsychotics ◽  
Receptor Sites ◽  
Receptor Profile ◽  
Dopamine Hypothesis ◽  
The Relationship

AbstractAtypical antipsychotics—clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole—differ from conventional antipsychotics primarily by virtue of their actions at multiple central receptor sites. Each agent has its own unique receptor profile. The discovery of dopaminergic receptor-blocking capabilities of conventionblockingal antipsychotic drugs led to the dopamine hypothesis of schizophrenia. More recently, the role of serotonergic and other receptors in the pathophysiology and symptomology of schizophrenia and schizoaffective disorder has been identified, and the receptor actions of atypical antipsychotics have been linked to both antipsychotic efficacy and the propensity for extrapyramidal symptoms and other adverse effects. Receptor occupancy is directly related to antipsychotic dose, and the nature of the relationship between clinical utility and receptor occupancy is beginning to emerge. As our understanding of this relationship becomes more clear, the mechanism underlying clinical distinctions between agents will be understood.

scholarly journals Determination of receptor occupancy in the presence of mass dose: [11C]GSK189254 PET imaging of histamine H3 receptor occupancy by PF-03654746

2016 ◽  
Vol 37 (3) ◽  
pp. 1095-1107 ◽  
Author(s):  
Jean-Dominique Gallezot ◽  
Beata Planeta ◽  
Nabeel Nabulsi ◽  
Donna Palumbo ◽  
Xiaoxi Li ◽  
...  
Keyword(s):  
Binding Sites ◽  
Human Subjects ◽  
Receptor Occupancy ◽  
Healthy Human ◽  
Positron Emission ◽  
Relationship Of ◽  
The Relationship ◽  
Pet Scans

Measurements of drug occupancies using positron emission tomography (PET) can be biased if the radioligand concentration exceeds “tracer” levels. Negative bias would also arise in successive PET scans if clearance of the radioligand is slow, resulting in a carryover effect. We developed a method to (1) estimate the in vivo dissociation constant Kd of a radioligand from PET studies displaying a non-tracer carryover (NTCO) effect and (2) correct the NTCO bias in occupancy studies taking into account the plasma concentration of the radioligand and its in vivo Kd. This method was applied in a study of healthy human subjects with the histamine H3 receptor radioligand [11C]GSK189254 to measure the PK-occupancy relationship of the H3 antagonist PF-03654746. From three test/retest studies, [11C]GSK189254 Kd was estimated to be 9.5 ± 5.9 pM. Oral administration of 0.1 to 4 mg of PF-03654746 resulted in occupancy estimates of 71%–97% and 30%–93% at 3 and 24 h post-drug, respectively. NTCO correction adjusted the occupancy estimates by 0%–15%. Analysis of the relationship between corrected occupancies and PF-03654746 plasma levels indicated that PF-03654746 can fully occupy H3 binding sites ( ROmax = 100%), and its IC50 was estimated to be 0.144 ± 0.010 ng/mL. The uncorrected IC50 was 26% higher.

In Vivo Assay for Neuroleptic Receptor Binding in the Striatum

1987 ◽  
Vol 151 (6) ◽  
pp. 824-830 ◽  
Author(s):  
H. Cambon ◽  
J. C. Baron ◽  
J. P. Boulenger ◽  
C. Loc'h ◽  
E. Zarifian ◽  
...  
Keyword(s):  
Corpus Striatum ◽  
Specific Binding ◽  
Receptor Occupancy ◽  
Saturation Curve ◽  
Validity And Reliability ◽  
Neuroleptic Treatment ◽  
Clear Cut ◽  
Therapeutic Doses ◽  
Dose Dependent

Using PET, we investigated the potency in six patients of therapeutic doses of neuroleptic drugs for preventing specific binding of trace doses of intravenously administered 76Br labelled bromospiperone to corpus striatum in vivo. Measured receptor occupancy showed a clear-cut dose-dependent saturation curve with increasing daily oral dose of neuroleptics, indicating the validity and reliability of the method when used as an in vivo radioreceptor assay. Following drug withdrawal in eight patients, recovery to normal or supranormal receptor availability occurred in a matter of days. The results demonstrate an approach that may help resolve controversies about, and design better strategies for, neuroleptic treatment schedules.

scholarly journals Olanzapine: Association Between a Typical Antipsychotic Drug and Aortic Calcification

2021 ◽  
Vol 8 ◽  
Author(s):  
Chao Zhang ◽  
Dongdong Zheng ◽  
Weijing Feng ◽  
Huanji Zhang ◽  
Feng Han ◽  
...  
Keyword(s):  
Antipsychotic Drug ◽  
Antipsychotic Drugs ◽  
Equivalent Dose ◽  
Aortic Calcification ◽  
Typical Antipsychotic ◽  
Negatively Associated ◽  
Olanzapine Treatment ◽  
Defined Daily Doses ◽  
The Relationship

Aims: This study concentrates on the relationship between antipsychotic drugs (APDs) and aortic calcification.Methods: All 56 patients with schizophrenia were divided into two groups according to aortic calcification index. APD equivalent dose was calculated via defined daily doses method.Results: In schizophrenia patients with higher aortic calcification index scores, APD equivalent doses were lower. APD equivalent dose was negatively related to aortic calcification index. Although equivalent APD dose in patients without olanzapine treatment was negatively related to aortic calcification index, it seems that equivalent APD dose did not associate with aortic calcification.Conclusion: Aortic calcification is negatively associated with APD dose in schizophrenia patients. Olanzapine seems to be vital to the relationship between aortic calcification and APD treatment.

Typical antipsychotic drugs — D2 receptor occupancy and depressive symptoms in schizophrenia

2002 ◽  
Vol 56 (1-2) ◽  
pp. 31-36 ◽  
Author(s):  
Rodrigo A Bressan ◽  
Durval C Costa ◽  
Hugh M Jones ◽  
Peter J Ell ◽  
Lyn S Pilowsky
Keyword(s):  
Depressive Symptoms ◽  
Antipsychotic Drugs ◽  
D2 Receptor ◽  
Receptor Occupancy ◽  
Typical Antipsychotic

Characterization by saturation studies of the in vivo binding of [3H]flunitrazepam in mouse brain

1991 ◽  
Vol 69 (2) ◽  
pp. 176-180 ◽  
Author(s):  
Peter T.-H. Wong
Keyword(s):  
Mouse Brain ◽  
Incubation Temperature ◽  
Specific Binding ◽  
Protein A ◽  
Receptor Occupancy ◽  
Acute Tolerance ◽  
Alternative Methods ◽  
In Vivo Binding

The in vivo binding of [3H]flunitrazepam ([3H]Fln) was characterized in seven regions of the mouse brain. The binding showed saturability and linear Scatchard plots. Hill coefficients were close to unity. Data fitting to a hyperbola by least squares yielded consistent Kd values for all regions studied (0.36–0.6 pmol/mg protein). Bmax values ranged from 0.14 to 0.89 pmol/mg protein, a sixfold regional variation. The order of binding is as follows: cortex > hippocampus > midbrain = thalamus/hypothalamus > striatum ≥ cerebellum > brainstem, consistent with that obtained by in vitro binding. The in vivo receptor density and affinity are apparently lower in comparison with in vitro parameters. This is consistent with the observation that the Kd increases and Bmax decreases in vitro when the incubation temperature is increased from 0 °C. Non-specific binding has been estimated by displacement of in vivo binding by unlabelled ligand in vitro as well as by pretreatment with unlabelled ligand. The two alternative methods were compared and evaluated. It is concluded that the displacement method provides more reliable estimates of the nonspecific binding. Diazepam-sensitive mice did not differ from the control mice in the in vivo [3H]Fln binding. However, mice pretreated with diazepam 1 or 2 days before have binding reduced by 70 or 30%, respectively. The reduced binding may be explained by receptor occupancy by residual oxazepam. However, the low concentration of the residual oxazepam is an unlikely cause of the phenomenon of "acute tolerance" observed in these mice.Key words: benzodiazepines, in vivo binding, characterization, diazepam-sensitive mice, acute tolerance.

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