Increased Cerebral Blood Flow after single dose of antipsychotics in healthy volunteers depends on dopamine D2 receptor density profiles
| Autor: | Peter C.T. Hawkins, Pierluigi Selvaggi, Juergen Dukart, Steven Williams, Mitul A. Mehta, Ottavia Dipasquale, Fabio Sambataro, Alessandro Bertolino, Federico Turkheimer, Mattia Veronese, Gaia Rizzo, Fernando Zelaya, Giulio Pergola |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Fluorine Radioisotopes
medicine.medical_treatment Hemodynamics DR 0302 clinical medicine Antipsychotics ASL CBF D 2 R DRD2 mRNA expression PET D2R 0303 health sciences education.field_of_study Cross-Over Studies 05 social sciences Brain Human brain Risperidone Healthy Volunteers Dopamine D2 Receptor Antagonists medicine.anatomical_structure Neurology Cerebral blood flow Fallypride Olanzapine Cerebrovascular Circulation Benzamides Antipsychotic Agents Adult medicine.medical_specialty Cognitive Neuroscience Population 050105 experimental psychology 03 medical and health sciences Double-Blind Method Dopamine receptor D2 Internal medicine medicine Humans 0501 psychology and cognitive sciences RNA Messenger education Antipsychotic 030304 developmental biology Receptors Dopamine D2 business.industry Binding potential Endocrinology Positron-Emission Tomography Haloperidol Spin Labels business 030217 neurology & neurosurgery |
| Zdroj: | Selvaggi, P, Hawkins, P C T, Dipasquale, O, Rizzo, G, Bertolino, A, Dukart, J, Sambataro, F, Pergola, G, Williams, S C R, Turkheimer, F, Zelaya, F, Veronese, M & Mehta, M A 2019, ' Increased cerebral blood flow after single dose of antipsychotics in healthy volunteers depends on dopamine D2 receptor density profiles ', NeuroImage, vol. 188, no. 0, pp. 774-784 . https://doi.org/10.1016/j.neuroimage.2018.12.028 |
| DOI: | 10.1101/336933 |
| Popis: | As 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 p2R 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. |
| Databáze: | OpenAIRE |
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