Journal Article

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

Veronese, Mattia, Selvaggi, Pierluigi, Mehta, Mitul A., Gabay, Anthony S., Dipasquale, Ottavia, Turkheimer, Federico

2019

Overview

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-HT1A, 5-HT1B, 5-HT2A, and 5-HT4) 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-HT1A distribution density maps, which are the main targets of this compound. Changes in the 5-HT1A-enriched functional maps were also associated with the pharmacokinetic levels of MDMA and MDMA-induced FC changes in the 5-HT2A-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. [Display omitted] •MDMA connectivity effects understood through the distribution of 5-HT1A and 5-HTT.•Direct link between PK levels of MDMA and 5-HT1A-enriched functional connectivity maps.•Ability to link receptor targets to functional mechanisms underlying behaviour.•Mapping pharmacodynamic effects onto the drug's molecular targets.

• Publisher: Elsevier Inc,Elsevier Limited,Academic Press
• Subject: Acute effects / Adult / Brain - drug effects / Brain mapping / Brain research / Cross-Over Studies / Dopamine / Double-Blind Method / Ecstasy / Female / Functional connectivity / Functional magnetic resonance imaging / Humans / Investigations / Male / MDMA / Medical imaging / N-Methyl-3,4-methylenedioxyamphetamine - pharmacology / Neural networks / Neuroimaging - methods / Pharmacodynamic response / Pharmacodynamics / Pharmacological neuroimaging / Pharmacology / Positron emission tomography / Positron-Emission Tomography - methods / Resting state fMRI / Serotonin / Serotonin Agents - pharmacology / Serotonin receptors / Serotonin S1 receptors / Serotonin S2 receptors / Serotonin S4 receptors / Young Adult