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Unravelling the effects of methylphenidate on the dopaminergic and noradrenergic functional circuits

Dipasquale, Ottavia, Martins, Daniel, Sethi, Arjun, Veronese, Mattia, Hesse, Swen, Rullmann, Michael, Sabri, Osama, Turkheimer, Federico, Harrison, Neil A., Mehta, Mitul and Cercignani, Mara 2020. Unravelling the effects of methylphenidate on the dopaminergic and noradrenergic functional circuits. Neuropsychopharmacology 45 , pp. 1482-1489. 10.1038/s41386-020-0724-x

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Abstract

Functional magnetic resonance imaging (fMRI) can be combined with drugs to investigate the system-level functional responses in the brain to such challenges. However, most psychoactive agents act on multiple neurotransmitters, limiting the ability of fMRI to identify functional effects related to actions on discrete pharmacological targets. We recently introduced a multimodal approach, REACT (Receptor-Enriched Analysis of functional Connectivity by Targets), which offers the opportunity to disentangle effects of drugs on different neurotransmitters and clarify the biological mechanisms driving clinical efficacy and side effects of a compound. Here, we focus on methylphenidate (MPH), which binds to the dopamine transporter (DAT) and the norepinephrine transporter (NET), to unravel its effects on dopaminergic and noradrenergic functional circuits in the healthy brain at rest. We then explored the relationship between these target-enriched resting state functional connectivity (FC) maps and inter-individual variability in behavioural responses to a reinforcement-learning task encompassing a novelty manipulation to disentangle the molecular systems underlying specific cognitive/behavioural effects. Our main analysis showed a significant MPH-induced FC increase in sensorimotor areas in the functional circuit associated with DAT. In our exploratory analysis, we found that MPH-induced regional variations in the DAT and NET-enriched FC maps were significantly correlated with some of the inter-individual differences on key behavioural responses associated with the reinforcement-learning task. Our findings show that main MPH-related FC changes at rest can be understood through the distribution of DAT in the brain. Furthermore, they suggest that when compounds have mixed pharmacological profiles, REACT may be able to capture regional functional effects that are underpinned by the same cognitive mechanism but are related to engagement of distinct molecular targets.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Springer Nature
ISSN: 0893-133X
Date of First Compliant Deposit: 21 May 2020
Date of Acceptance: 15 May 2020
Last Modified: 18 Jan 2021 21:10
URI: http://orca.cf.ac.uk/id/eprint/131861

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