Clinically Relevant Doses of Methylphenidate Significantly Occupy Norepinephrine Transporters in Humans In Vivo
| Autor: | Jean-Dominique Gallezot, Wendol Williams, Robert T. Malison, Beata Planeta-Wilson, Christopher H. van Dyck, Jonas Hannestad, Yu-Shin Ding, Shu-fei Lin, Richard E. Carson |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
Male Morpholines Pharmacology Article Radioligand Assay Reboxetine Dopamine medicine Humans Attention deficit hyperactivity disorder Biological Psychiatry Dopamine transporter Norepinephrine Plasma Membrane Transport Proteins Dose-Response Relationship Drug biology Methylphenidate Maintenance dose business.industry Brain medicine.disease Magnetic Resonance Imaging Effective dose (pharmacology) Norepinephrine transporter Positron-Emission Tomography Anesthesia biology.protein Central Nervous System Stimulants Female business medicine.drug |
| Zdroj: | Biological Psychiatry. 68:854-860 |
| ISSN: | 0006-3223 |
| DOI: | 10.1016/j.biopsych.2010.06.017 |
| Popis: | 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)-[ 11 C] methylreboxetine ([ 11 C]MRB) to determine the effective dose 50 (ED 50 ) 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 [ 11 C]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 ED 50 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 ED 50 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. |
| Databáze: | OpenAIRE |
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