O4.3. INCREASED CEREBRAL BLOOD FLOW AFTER SINGLE DOSE OF ANTIPSYCHOTICS IN HEALTHY SUBJECTS DEPENDS ON DOPAMINE D2 RECEPTOR DENSITY PROFILES EVALUATED WITH PET AND MRNA EXPRESSION DATA.

AbstractAs a result of neuro-vascular coupling, the functional effects of antipsychotics in human brain have been investigated in both healthy and clinical populations using haemodynamic markers such as regional Cerebral Blood Flow (rCBF). However, the relationship between observed haemodynamic effects and the pharmacological action of these drugs has not been fully established. Here, we analysed MRI-based rCBF data from a placebo-controlled study in healthy volunteers, who received a single dose of three different D2 receptor antagonists and tested the association of the main effects of the drugs on rCBF against normative population maps of D2R protein density and gene-expression data. In particular, we correlated CBF changes after antipsychotic administration with non-displaceable binding potential (BPND) template maps of the high affinity D2-antagonist Positron Emission Tomography (PET) ligand [18F]Fallypride and brain post-mortem microarray mRNA expression data for the DRD2 gene. For all antipsychotics, rCBF changes were directly proportional to brain D2R densities and DRD2 mRNA expression measures, although PET BPND spatial profiles explained more variance as compared with mRNA profiles (PET R2 range= 0.20-0.60, mRNA PET R2 range 0.04-0.20, pairwise-comparisons all p<0.05). In addition, the spatial coupling between ΔCBF and D2R profiles varied between the different antipsychotics tested, possibly reflecting differential affinities. Overall, these results indicate that the functional effects of antipsychotics as measured with rCBF are tightly correlated with the distribution of their target receptors in striatal and extra-striatal regions. Our results further demonstrate the link between neurotransmitter targets and haemodynamic changes reinforcing rCBF as a robust in-vivo marker of drug effects. This work is important in bridging the gap between pharmacokinetic and pharmacodynamics of novel and existing compounds.

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Can Cerebral Blood Volume Be Measured Reproducibly with an Improved near Infrared Spectroscopy System?

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200102000-00002 ◽

2001 ◽

Vol 21 (2) ◽

pp. 110-113 ◽

Cited By ~ 15

Author(s):

Marjo J. T. Van de Ven ◽

Willy N. J. M. Colier ◽

Marco C. van der Sluijs ◽

Diederik Walraven ◽

Berend Oeseburg ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Infrared Spectroscopy ◽

Blood Volume ◽

Near Infrared Spectroscopy ◽

Healthy Subjects ◽

Baseline Level ◽

Near Infrared ◽

Cerebral Blood Volume ◽

Spectroscopy System

In some circumstances, cerebral blood volume (CBV) can be used as a measure for cerebral blood flow. A new near infrared spectroscope was used for determining the reproducibility of CBV measurements assessed by the O2-method. Twenty-seven healthy subjects were investigated. An intrasubject coefficient of variation (CV) was calculated, based on four identical episodes of desaturation–resaturation (O2-method) procedures for CBV measurements. Two trials were performed, with (trial 1) and without (trial 2) disconnecting the equipment. A mean CV of 12.6% and 10.0% was found in trial 1 and 2, respectively. Cerebral blood volume values yield 3.60 ± 0.82 mL 100 g−1. Cerebral blood volume could be measured reproducible in adults using near infrared spectroscopy, if the arterial desaturation is limited to approximately 5% from baseline level.

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Effect of acetazolamide on cerebral blood flow and tympanic temperature in healthy subjects and patients with subacute subarachnoid haemorrhage

European Journal of Applied Physiology ◽

10.1007/s004210050156 ◽

1997 ◽

Vol 75 (3) ◽

pp. 252-255 ◽

Cited By ~ 3

Author(s):

Fumihiko Sugino ◽

Tokuo Ogawa ◽

Satoshi Umemura ◽

Satoru Suzuki ◽

Yasuhiro Kawamura

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Subarachnoid Haemorrhage ◽

Healthy Subjects ◽

Tympanic Temperature

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An intronic polymorphism in the PAR-1 gene is associated with platelet receptor density and the response to SFLLRN

Blood ◽

10.1182/blood-2002-07-2149 ◽

2003 ◽

Vol 101 (5) ◽

pp. 1833-1840 ◽

Cited By ~ 79

Author(s):

Annabelle Dupont ◽

Pierre Fontana ◽

Christilla Bachelot-Loza ◽

Jean-Luc Reny ◽

Ivan Bièche ◽

...

Keyword(s):

Allelic Frequency ◽

Interindividual Variation ◽

Expression Data ◽

Receptor Density ◽

Platelet Response ◽

Platelet Surface ◽

Mrna Expression Data ◽

Intronic Polymorphism ◽

Platelet Receptor ◽

Protease Activated Receptor 1

Protease-activated receptor 1 (PAR-1), the main thrombin receptor on vascular cells, plays a key role in platelet activation. We examined the range of PAR-1 expression on platelets, obtained twice, 1 week apart, from 100 healthy subjects and found a 2-fold interindividual variation in receptor numbers (95% CI = 858-1700). Because PAR-1 density was stable with time (r2 = 76%,P < .001), we sought a genetic explanation for the observed variability. To validate this approach, we also analyzed the α2β1 genotype according to receptor density and platelet mRNA expression data. We found that the number of PAR-1 receptors on the platelet surface is associated with the intervening sequence IVSn−14 A/T intronic variation. The number of receptors was also found to govern the platelet response to the SFLLRN agonist, in terms of aggregation and P-selectin expression. The T allele (allelic frequency, 0.14) can be considered as an allele with decreased expression, because it was associated with lower PAR-1 expression on the platelet surface and with a lower response to SFLLRN. The IVSn−14 A/T intronic variation may therefore be clinically relevant.

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Abstract WP322: Inhaled Nitric Oxide Augments Cerebral Blood Flow in Healthy Subjects

Stroke ◽

10.1161/str.49.suppl_1.wp322 ◽

2018 ◽

Vol 49 (Suppl_1) ◽

Author(s):

Christopher G Favilla ◽

Rodrigo M Forti ◽

Ahmad Zamzam ◽

John A Detre ◽

Michael T Mullen ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Healthy Subjects ◽

Inhaled Nitric Oxide

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The Acute and Chronic Cognitive and Cerebral Blood-Flow Effects of Nepalese Pepper (Zanthoxylum armatum DC.) Extract—A Randomized, Double-Blind, Placebo-Controlled Study in Healthy Humans

Nutrients ◽

10.3390/nu11123022 ◽

2019 ◽

Vol 11 (12) ◽

pp. 3022 ◽

Cited By ~ 3

Author(s):

David Kennedy ◽

Emma Wightman ◽

Julie Khan ◽

Torsten Grothe ◽

Philippa Jackson

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Single Dose ◽

Frontal Cortex ◽

Task Performance ◽

Performance Measure ◽

Controlled Study ◽

Double Blind ◽

Zanthoxylum Armatum ◽

Healthy Humans

Background: Zanthoxylum armatum DC. (ZA) is a traditional Asian culinary spice and medicinal compound, which is rich in monoterpenes and hydroxy α-sanshool. Mechanistic interactions with the monoamine, cholinergic and cannabinoid neurotransmission systems, as well as transient receptor potential (TRP) and potassium ion channels, may predispose ZA to modulate human brain function. Objectives: To investigate the effects of a single dose and 56-days supplementation with a lipid extract of ZA on cognitive function, mood and cerebral blood-flow (CBF) parameters in the pre-frontal cortex during cognitive task performance. Design: Double-blind, randomized, parallel groups study with N = 82 healthy males and females between the ages of 30 and 55 years. Assessments were undertaken pre-dose and at 1, 3 and 5 h post-dose on the first (Day 1) and last (Day 56) days of supplementation. Results: A single dose of ZA (Day 1) resulted in acute improvements on a ‘Speed of Attention’ factor and the Rapid Visual Information Processing (RVIP) task, in comparison to placebo. However, following ZA participants were less accurate on the name-to-face recall task. After 56 days of ZA consumption (Day 56), speed was enhanced on a global ‘Speed of Performance’ measure, comprising data from all of the timed tasks in the computerized battery. Participants also completed more correct Serial 3s Subtractions at the 3 h assessment and were less mentally fatigued throughout the day than participants consuming placebo. These effects were complemented on both Day 1 and Day 56 by modulation of CBF parameters, as assessed by Near Infrared Spectroscopy (NIRS). The primary finding here was a reduced hemodynamic response during the RVIP task. Conclusion: ZA improves aspects of cognitive performance, in particular the speed of performing tasks, in healthy humans and results in concomitant reductions in hemodynamic responses in the frontal cortex during task performance. The findings suggest an increase in neural efficiency following ZA.

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Population Pharmacokinetics of JNJ-37822681, a Selective Fast-Dissociating Dopamine D2-Receptor Antagonist, in Healthy Subjects and Subjects with Schizophrenia and Dose Selection Based on Simulated D2-Receptor Occupancy

Clinical Pharmacokinetics ◽

10.1007/s40262-013-0084-3 ◽

2013 ◽

Vol 52 (11) ◽

pp. 1005-1015 ◽

Cited By ~ 3

Author(s):

Eef Hoeben ◽

Martine Neyens ◽

Erik Mannaert ◽

Mark Schmidt ◽

An Vermeulen

Keyword(s):

Receptor Antagonist ◽

Population Pharmacokinetics ◽

Healthy Subjects ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Receptor Occupancy ◽

Dose Selection ◽

Dopamine D2 ◽

Dopamine D2 Receptor Antagonist

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A Double-Injection Technique for in vivo Measurement of Dopamine D2-Receptor Density in Monkeys with 3-(2'-[18F] Fluoroethyl)Spiperone and Dynamic Positron Emission Tomography

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1989.119 ◽

1989 ◽

Vol 9 (6) ◽

pp. 850-858 ◽

Cited By ~ 31

Author(s):

Sung-Cheng Huang ◽

Mark M. Bahn ◽

Jorge R. Barrio ◽

John M. Hoffman ◽

Nagichettiar Satyamurthy ◽

...

Keyword(s):

Positron Emission Tomography ◽

Receptor Binding ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Emission Tomography ◽

Injection Technique ◽

Receptor Density ◽

Dopamine D2 ◽

Positron Emission ◽

Kinetics Of

Dopamine D2-receptor density in striatum of monkey was measured with 3-(2'-[18F]fluoroethyl)spiperone (FESP) and dynamic positron emission tomography (PET), using a double-injection technique. A first bolus of high specific activity (SA) FESP (5 mCi; ≃ 1 Ci/μmol) was injected i.v.; 90 min later, a second bolus of lower SA FESP (5 mCi; ≃ 0.04 Ci/μmol) was injected. A dynamic PET study was performed to measure the kinetics of FESP in striatum over 180 min, and the metabolite-corrected concentration of FESP in plasma as a function of time was obtained from arterial blood samples. A nonlinear compartmental model that took into account the saturability of the receptor binding was used to describe the kinetics of FESP in striatum. Model parameters were estimated by regression with a constraint based on information about the equilibrium dissociation constant of the ligand–receptor binding. Dopamine D2-receptor density in striatum was estimated to be 25.9 ± 12.7 pmol/g in seven Macaca nemestrina monkeys. The method does not require the use of cerebellum as a reference tissue region and an estimate of dopamine D2-receptor density can be obtained from a single study.

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