title: Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro.
abstract: 2-[(Diphenylmethyl) sulfinyl]acetamide (modafinil), prescribed principally to treat narcolepsy, is undergoing assessment for other neuropsychiatric disorders and medical conditions. The neurochemical substrates of modafinil are unresolved. We postulated that modafinil enhances wakefulness by modulating dopamine (DAT), norepinephrine (NET), or serotonin (SERT) transporter activities. In vivo, we determined DAT and NET occupancy by modafinil by positron emission tomography imaging; in vitro, we determined modafinil activity at the DAT, NET, SERT, and rhesus monkey trace amine receptor 1 (TA1). In rhesus monkey, modafinil occupancy of striatal DAT was detected by [(11)C]2beta-carbomethoxy-3beta-4-(fluorophenyl)tropane and of thalamic NET by [(11)C](S,S)-2-(alpha-(2-methoxyphenoxy)-benzyl)morpholine. In vitro, modafinil effects in DAT-human embryonic kidney (HEK), NET-HEK, and SERT-HEK cells were investigated alone or combined with the TA1 receptor. Modafinil (i.v.) occupied striatal DAT sites (5 mg/kg: 35 +/- 12%, n = 4; 8 mg/kg: 54 +/- 3%, n = 3). In thalamus, modafinil occupied NET sites (5 mg/kg: 16 +/- 7.8%, n = 6; 8 mg/kg: 44 +/- 12%; n = 2). In vitro, modafinil inhibited [(3)H]dopamine (IC(50) = 6.4 microM), [(3)H]norepinephrine (IC(50) = 35.6 microM), and [(3)H]serotonin (IC(50) > 500 microM) transport via the human DAT, NET, and SERT. Modafinil did not activate the TA1 receptor in TA1-HEK cells, but it augmented a monoamine transporter-dependent enhancement of phenethylamine activation of TA1 in TA1-DAT and TA1-NET cells, but not in TA1-SERT cells. The present data provide compelling evidence that modafinil occupies the DAT and NET in living brain of rhesus monkeys and raise the possibility that modafinil affects wakefulness by interacting with catecholamine transporters in brain.
authors.affiliation: Department of Psychiatry, Harvard Medical School, New England Primate Research Center, 1 Pine Hill Dr., Southborough, MA 01772-9102, USA. bertha_madras@hms.harvard.edu
authors.forename: Bertha K
authors.initials: BK
authors.lastname: Madras
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Xie
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Lin
authors.forename: Amy
authors.initials: A
authors.lastname: Jassen
authors.forename: Helen
authors.initials: H
authors.lastname: Panas
authors.forename: Laurie
authors.initials: L
authors.lastname: Lynch
authors.forename: Ryan
authors.initials: R
authors.lastname: Johnson
authors.forename: Eli
authors.initials: E
authors.lastname: Livni
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Spencer
authors.forename: Ali A
authors.initials: AA
authors.lastname: Bonab
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Miller
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Fischman
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D008253:Macaca mulatta; D008297:Male; D000077408:Modafinil; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D010627:Phenethylamines / Q000494:pharmacology; D049268:Positron-Emission Tomography; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects; D000095383:Trace Amine-Associated Receptors
chemical_list: D001559:Benzhydryl Compounds; D004298:Dopamine; D050483:Dopamine Plasma Membrane Transport Proteins; D000077408:Modafinil; D009638:Norepinephrine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010627:Phenethylamines; D043562:Receptors, G-Protein-Coupled; D050486:Serotonin Plasma Membrane Transport Proteins; D000095383:Trace Amine-Associated Receptors