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

Selvaggi, Pierluigi; Hawkins, Peter Ct; Dipasquale, Ottavia; Rizzo, Gaia; Bertolino, Alessandro; Dukart, Juergen; Sambataro, Fabio; Pergola, Giulio; Williams, Steven; Turkheimer, Federico; Zelaya, Fernando; Veronese, Mattia; Mehta, Mitul A.

doi:10.1016/j.neuroimage.2018.12.028

Cited by 35 publications

(34 citation statements)

References 72 publications

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“…Assuming affinity to a certain target is constant across regions, this basic pharmacology principle predicts that brain regions of high density of the target receptor will show higher magnitude of drug effects. This relationship has been demonstrated for compounds targeting the dopamine, glutamate, serotonin and GABA systems 116,117 . However, we are still unclear about whether and how the physiological brain changes (i.e.…”

Section: Relationship Between Intranasal Oxytocin-induced Changes In Rcbf and The Expression Of Oxtr Mrnamentioning

confidence: 85%

“Less is more”: a dose-response account of intranasal oxytocin pharmacodynamics in the human brain

Martins

Broadmann

Veronese

et al. 2021

Preprint

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The potential of intranasal oxytocin to treat several brain disorders is hampered by questions regarding the most effective dose to engage central targets and the validity of haemodynamic neuroimaging to capture its effects on neuronal activity. Using a dose-response design (9, 18 and 36 IU), we demonstrate that resting oxytocin-induced physiological changes in the amygdala, a key-hub of the brain oxytocin system, are consistent with an inverted-U dose-response curve, with maximal effects for lower doses. Yet, the effects of oxytocin vary by amygdala subdivision, highlighting the need to qualify dose-response curves within region. We further link physiological changes with the density of the oxytocin receptor gene mRNA across brain regions, strengthening our confidence in intranasal oxytocin as a valid approach to target central targets. We also demonstrate that intranasal oxytocin does not disrupt cerebrovascular reactivity, corroborating the validity of haemodynamic neuroimaging to probe its effects on the human brain.

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Section: Relationship Between Intranasal Oxytocin-induced Changes In Rcbf and The Expression Of Oxtr Mrnamentioning

confidence: 85%

“Less is more”: a dose-response account of intranasal oxytocin pharmacodynamics in the human brain

Martins

Broadmann

Veronese

et al. 2021

Preprint

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“…The integration between haemodynamic markers and molecular imaging data is still a challenge. Some studies investigated the spatial association between the main effects of different drugs on the CBF and the molecular information from gene-expression, PET or autoradiography data using simple ROI-to-ROI correlations (Dukart et al., 2018; Selvaggi et al., 2018). While this approach has proven its efficacy with ASL data sets, it would be over simplistic if applied to rs-fMRI data, since the temporal dynamics of the BOLD signal would be overlooked.…”

Section: Discussionmentioning

confidence: 99%

Receptor-Enriched Analysis of functional connectivity by targets (REACT): A novel, multimodal analytical approach informed by PET to study the pharmacodynamic response of the brain under MDMA

et al. 2019

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One of the main limitations of pharmacological fMRI is its inability to provide a molecular insight into the main effect of compounds, leaving an open question about the relationship between drug effects and haemodynamic response. The aim of this study is to investigate the acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on functional connectivity (FC) using a novel multimodal method (Receptor-Enriched Analysis of functional Connectivity by Targets - REACT). This approach enriches the resting state (rs-)fMRI analysis with the molecular information about the distribution density of serotonin receptors in the brain, given the serotonergic action of MDMA. Twenty healthy subjects participated in this double-blind, placebo-controlled, crossover study. A high-resolution in vivo atlas of four serotonin receptors (5-HT 1A , 5-HT 1B , 5-HT 2A , and 5-HT 4 ) and its transporter (5-HTT) was used as a template in a two-step multivariate regression analysis to estimate the spatial maps reflecting the whole-brain connectivity behaviour related to each target under placebo and MDMA. Results showed that the networks exhibiting significant changes after MDMA administration are the ones informed by the 5-HTT and 5-HT 1A distribution density maps, which are the main targets of this compound. Changes in the 5-HT 1A -enriched functional maps were also associated with the pharmacokinetic levels of MDMA and MDMA-induced FC changes in the 5-HT 2A -enriched maps correlated with the spiritual experience subscale of the Altered States of Consciousness Questionnaire. By enriching the rs-fMRI analysis with molecular data of voxel-wise distribution of the serotonin receptors across the brain, we showed that MDMA effects on FC can be understood through the distribution of its main targets. This result supports the ability of this method to characterise the specificity of the functional response of the brain to MDMA binding to serotonergic receptors, paving the way to the definition of a new fingerprint in the characterization of new compounds and potentially to a further understanding to the response to treatment.

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“…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.…”

Section: Conclusion From the Application Examplesmentioning

confidence: 67%

“…Whilst 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 et al, 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.…”

Section: Introductionmentioning

confidence: 99%

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

Dukart

Holiga

Rullmann

et al. 2020

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Recent studies have shown that drug-induced spatial alteration patterns in resting state functional activity as measured using magnetic resonance imaging (MRI) are associated with the distribution of specific receptor systems targeted by respective compounds. Based on this approach, we introduce a Matlab-based toolbox (JuSpace) allowing for cross-modal correlation of MRI-based measures with positron emission tomography (PET) and single photon emission computed tomography (SPECT) derived estimates covering various receptor systems including dopaminergic, serotonergic, noradrenergic, and GABAergic (gamma-aminobutric acid) neurotransmission. We apply JuSpace to two datasets covering Parkinson's disease patients (PD) on and off levodopa and risperidone-induced changes in rsfMRI and cerebral blood flow (CBF). We correlate rsfMRI derived PD-and levodopa-induced local activity alterations with PET and SPECT maps covering the above neurotransmitter systems.Similarly, we correlate the effects of risperidone on CBF with respective maps. Consistently with the predominant neurodegeneration of dopaminergic and serotonergic system in PD, we find significant spatial associations between rsfMRI activity alterations in PD on and off levodopa and dopaminergic (D2) and serotonergic systems (5-HT1b). Consistently with its mechanism of action, risperidone induced CBF alterations were correlated with key targets of serotonergic and dopaminergic systems. The JuSpace toolbox provides an easy framework for correlation of spatial alteration patterns across different neuroimaging modalities with PET derived receptor maps. Taken together, toolbox allows for cross-modal biologically meaningful evaluation and interpretation of image-derived spatial alteration patterns.

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

Abstract: Increased cerebral blood flow after single dose of antipsychotics in healthy volunteers depends on dopamine D2 receptor density profiles. NeuroImage, 188, 774-784.

Cited by 35 publications

References 72 publications

“Less is more”: a dose-response account of intranasal oxytocin pharmacodynamics in the human brain

“Less is more”: a dose-response account of intranasal oxytocin pharmacodynamics in the human brain

Receptor-Enriched Analysis of functional connectivity by targets (REACT): A novel, multimodal analytical approach informed by PET to study the pharmacodynamic response of the brain under MDMA

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

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