Increased cerebral blood flow after single dose of antipsychotics in healthy volunteers depends on dopamine D2 receptor density profiles

Publication date: Available online 13 December 2018

Source: NeuroImage

Author(s): Pierluigi Selvaggi, Peter C.T. Hawkins, Ottavia Dipasquale, Gaia Rizzo, Alessandro Bertolino, Juergen Dukart, Fabio Sambataro, Giulio Pergola, Steven C.R. Williams, Federico Turkheimer, Fernando Zelaya, Mattia Veronese, Mitul A. Mehta

Abstract

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 Arterial Spin Labelling (ASL) rCBF data from a placebo-controlled study in healthy volunteers, who received a single dose of three different D2 receptor (D₂R) 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 (BP_ND) template maps of the high affinity D₂-antagonist Positron Emission Tomography (PET) ligand [¹⁸F]Fallypride and with brain post-mortem microarray mRNA expression data for the DRD2 gene from the Allen Human Brain Atlas (ABA). For all antipsychotics, rCBF changes were directly proportional to brain D₂R densities and DRD2 mRNA expression measures, although PET BP_ND 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_corrected<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.

Graphical abstract

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