Cited by 236Attention Deficit Hyperactivity DisorderNeurotransmitter Receptor Influence on BehaviorSchizophrenia research and treatment

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Clinically Relevant Doses of Methylphenidate Significantly Occupy Norepinephrine Transporters in Humans In Vivo

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Hannestad, Jonas, Gallezot, Jean-Dominique, Planeta-Wilson, Beata, Lin, Shu-Fei, Williams, Wendol A., van Dyck, Christopher H., Malison, Robert T., Carson, Richard E., Ding, Yu-Shin·2010·Biological Psychiatry

DOI 10.1016/j.biopsych.2010.06.017PMC PMC3742016

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Abstract

Background Attention-deficit/hyperactivity disorder is a psychiatric disorder that starts in childhood. The mechanism of action of methylphenidate, the most common treatment for attention deficit hyperactivity disorder, is unclear. In vitro, the affinity of methylphenidate for the norepinephrine transporter (NET) is higher than that for the dopamine transporter (DAT). The goal of this study was to use positron emission tomography to measure the occupancy of brain norepinephrine transporter by methylphenidate in vivo in humans. Methods We used (S,S)-[¹¹C] methylreboxetine ([¹¹C]MRB) to determine the effective dose 50 (ED₅₀) of methylphenidate for NET. In a within-subject design, healthy subjects (n = 11) received oral, single-blind placebo and 2.5, 10, and 40 mg of methylphenidate 75 min before [¹¹C]MRB injection. Dynamic positron emission tomography imaging was performed for 2 hours with the High Resolution Research Tomograph. The multilinear reference tissue model with occipital cortex as the reference region was used to estimate binding potential non-displaceable (BP(ND)) in the thalamus and other NET-rich regions. Results BP(ND) was reduced by methylphenidate in a dose-dependent manner in thalamus and other NET-rich regions. The global ED₅₀ was estimated to be .14 mg/kg; therefore, the average clinical maintenance dose of methylphenidate (.35-.55 mg/kg) produces 70% to 80% occupancy of NET. Conclusions For the first time in humans, we demonstrate that oral methylphenidate significantly occupies NET at clinically relevant doses. The ED₅₀ is lower than that for DAT (.25 mg/kg), suggesting the potential relevance of NET inhibition in the therapeutic effects of methylphenidate in attention-deficit/hyperactivity disorder.

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Authors: Hannestad, J., Gallezot, J.-D., Planeta-Wilson, B., Lin, S.-F., Williams, W. A., van Dyck, C. H., Malison, R. T., Carson, R. E., & Ding, Y.-S.
Affiliations: Yale University (US)
Corresponding author: Ding, Yu-Shin
ORCID: Hannestad, Jonas
Gallezot, Jean-Dominique
van Dyck, Christopher H.
Malison, Robert T.
Carson, Richard E.
Ding, Yu-Shin
Venue: Biological Psychiatry
Publisher: Elsevier BV
Published: 2010-11
Volume: 68
Issue: 9
Pages: 854-860
ISSN: 0006-3223 (ISSN-L)
DOI: 10.1016/j.biopsych.2010.06.017
PMC: PMC3742016
OpenAlex: W2110412456
Cited by: 236
References: 41
Citations by year: 2026: 6 · 2025: 10 · 2024: 9 · 2023: 13 · 2022: 12 · 2021: 8 · 2020: 12 · 2019: 18 · 2018: 16 · 2017: 19 · 2016: 18 · 2015: 20 · 2014: 20 · 2013: 26 · 2012: 18
FWCI: 12.03
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Biological Psychiatry (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute on Drug Abuse (DA019062, R56DA19062)
National Center for Research Resources (UL1 RR024139)
National Institutes of Health, and National Institutes of Health roadmap for Medical Research (K12 DA000167)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords: methylphenidate, norepinephrine transporter, attention deficit hyperactivity disorder, dose-response relationship, thalamus, binding potential, dopamine transporter, mechanism of action
MeSH terms: Reboxetine, Adult, Central Nervous System Stimulants, Brain, Dose-Response Relationship, Drug, Female, Humans, Magnetic Resonance Imaging, Male, Methylphenidate, Morpholines, Radioligand Assay, Positron-Emission Tomography, Norepinephrine Plasma Membrane Transport Proteins

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Clinically Relevant Doses of Methylphenidate Significantly Occupy Norepinephrine Transporters in Humans In Vivo

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