title: Acute and sustained effects of methylphenidate on cognition and presynaptic dopamine metabolism: an [18F]FDOPA PET study.
abstract: Methylphenidate (MPH) inhibits the reuptake of dopamine and noradrenaline. PET studies with MPH challenge show increased competition at postsynaptic D2/3-receptors, thus indirectly revealing presynaptic dopamine release. We used [(18)F]fluorodopamine ([(18)F]FDOPA)-PET in conjunction with the inlet-outlet model (IOM) of Kumakura et al. (2007) to investigate acute and long-term changes in dopamine synthesis capacity and turnover in nigrostriatal fibers of healthy subjects with MPH challenge. Twenty healthy human females underwent two dynamic [(18)F]FDOPA PET scans (124 min; slow bolus-injection; arterial blood sampling), with one scan in untreated baseline condition and the other after MPH administration (0.5 mg/kg, p.o.), in randomized order. Subjects underwent cognitive testing at each PET session. Time activity curves were obtained for ventral putamen and caudate and were analyzed according to the IOM to obtain the regional net-uptake of [(18)F]FDOPA (K; dopamine synthesis capacity) as well as the [(18)F]fluorodopamine washout rate (kloss, index of dopamine turnover). MPH substantially decreased kloss in putamen (-22%; p = 0.003). In the reversed treatment order group (MPH/no drug), K was increased by 18% at no drug follow-up. The magnitude of K at the no drug baseline correlated with cognitive parameters. Furthermore, individual kloss changes correlated with altered cognitive performance under MPH. [(18)F]FDOPA PET in combination with the IOM detects an MPH-evoked decrease in striatal dopamine turnover, in accordance with the known acute pharmacodynamics of MPH. Furthermore, the scan-ordering effect on K suggested that a single MPH challenge persistently increased striatal dopamine synthesis capacity. Attenuation of dopamine turnover by MPH is linked to enhanced cognitive performance in healthy females.
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, 52074 Aachen, Germany, ischabram@ukaachen.de.
authors.forename: Ina
authors.initials: I
authors.lastname: Schabram
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Henkel
authors.affiliation: Department of Nuclear Medicine, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Siamak
authors.initials: S
authors.lastname: Mohammadkhani Shali
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Dietrich
authors.affiliation: Department of Nuclear Medicine, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Schmaljohann
authors.affiliation: Department of Nuclear Medicine, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Winz
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Zurich, 8006 Zurich, Switzerland.
authors.forename: Susanne
authors.initials: S
authors.lastname: Prinz
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, 52074 Aachen, Germany, Department of Child and Adolescent Psychiatry, University of Marburg, 35039 Marburg, Germany, and.
authors.forename: Lena
authors.initials: L
authors.lastname: Rademacher
authors.affiliation: Max-Planck-Institute for Neurological Research, 50931 Cologne, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Neumaier
authors.affiliation: Department of Anesthesiology, University Hospital of the RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Felzen
authors.affiliation: Department of Nuclear Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8654 Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kumakura
authors.affiliation: Department of Nuclear Medicine, University of Erlangen/Nürnberg, 91054 Erlangen, Germany, Department of Neuroscience and Pharmacology, Copenhagen University, 1165 Copenhagen, Denmark.
authors.forename: Paul
authors.initials: P
authors.lastname: Cumming
authors.affiliation: Department of Nuclear Medicine, RWTH Aachen University, 52074 Aachen, Germany, Jülich/Aachen Research Alliance, Jülich/Aachen, 52074 Aachen, Germany, Department of Nuclear Medicine, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands.
authors.forename: Felix M
authors.initials: FM
authors.lastname: Mottaghy
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, 52074 Aachen, Germany, Jülich/Aachen Research Alliance, Jülich/Aachen, 52074 Aachen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gründer
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, 52074 Aachen, Germany, Jülich/Aachen Research Alliance, Jülich/Aachen, 52074 Aachen, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Vernaleken
mesh_terms: D000328:Adult; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006801:Humans; D008774:Methylphenidate / Q000494:pharmacology*; D009483:Neuropsychological Tests; D011877:Radionuclide Imaging; D013378:Substantia Nigra / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D055815:Young Adult
chemical_list: D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D004298:Dopamine
keywords: [18F]FDOPA PET; cognition; dopamine turnover; long-term effects; methylphenidate; stimulants