Increased Cerebral Blood Flow after single dose of antipsychotics in healthy volunteers depends on dopamine D2 receptor density profiles

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 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 D 2 R 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 D 2 -antagonist Positron Emission Tomography (PET) ligand [ 18 F]Fallypride and brain post-mortem microarray mRNA expression data for the DRD2 gene. For all antipsychotics, rCBF changes were directly proportional to brain D 2 R densities and DRD2 mRNA expression measures, although PET BP ND spatial profiles explained more variance as compared with mRNA profiles (PET R 2 range= 0.20-0.60, mRNA PET R 2 range 0.04-0.20, pairwise-comparisons all p<0.05). In addition, the spatial coupling between ∆CBF and D 2 R 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.

Dopamine D2/3Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion

“…Interestingly, we also observed DA–BOLD associations in extrastriatal areas. This finding is in line with a recent study showing that both D 2 and D 3 receptor antagonists and agonists modulate blood flow changes in cortical areas (Black et al, 2002; Selvaggi et al, 2018; van den Brink et al, 2018). Indeed, it is well documented that dopaminergic terminals are located close to the cortical microvasculature and in vivo administration of DA causes a vasomotor response (Krimer et al, 1998).…”

Advances in simultaneous PET/MR for imaging neuroreceptor function

“…The link between D 2 neuroreceptor distribution, drug action and brain function, evaluated as changes in CBF, was also investigated in the context of antipsychotics: Given a single effective dose of an antipsychotic, an increase in striatal CBF was found that could also be correlated with receptor distribution and DRD2 mRNA expression profiles. 69 Consistent with other pharmacological studies, all four investigated antipsychotics showed a spatial neurovascular coupling to baseline receptor density profiles. A similar study that investigated seven clinical drugs relevant in psychiatry showed that coupling between receptors and neurovascular responses is applicable to several receptor targets.…”

JuSpace: A tool for spatial correlation analyses of magnetic resonance imaging data with nuclear imaging derived neurotransmitter maps

“…The strongest effects observed with low dose rather associate with DAT, SERT and D1 receptor maps. In our previous study (Selvaggi et al, 2018) we observed correlations with D2 receptors at both doses for the group averaged data. This study did not examine effects using other targets and did not evaluate individual differences.…”

“…While providing information about the spatial location of respective signals, such analyses do not allow drawing conclusions on potential neurophysiological mechanisms underlying the observed associations. To overcome this limitation, several recently published studies made use of spatial associations between underlying biology and observed imaging alterations by correlating ex vivo micro RNA spatial expression patterns with different imaging measures (Liu et al, 2019; Rizzo, Veronese, Expert, Turkheimer, & Bertoldo, 2016; Selvaggi et al, 2018). The major idea behind such analyses is that disease‐ or drug‐induced changes in imaging measures occur in association with availability of a specific tissue property (i.e., expression of a specific receptor) that is affected by the respective condition.…”