title: Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations.
abstract: OBJECTIVE
  There is increasing evidence that not only the monoaminergic but also the glutamatergic system is involved in the pathophysiology of attention-deficit hyperactivity disorder (ADHD). Hyperactivity of glutamate metabolism might be causally related to a hypoactive state in the dopaminergic system. Atomoxetine, a selective noradrenaline reuptake inhibitor, is the first non-stimulant approved for the treatment of this disorder. Here we have evaluated the effects of atomoxetine on glutamate receptors in vitro.
  
  
  METHODS
  The whole-cell configuration of the patch-clamp technique was used to analyse the effect of atomoxetine on N-methyl-d-aspartate (NMDA) receptors in cultured rodent cortical and hippocampal neurons as well as on NMDA receptors heterologously expressed in human TsA cells.
  
  
  RESULTS
  Atomoxetine blocked NMDA-induced membrane currents. Half-maximal inhibition emerged at about 3 microM which is in the range of clinically relevant concentrations found in plasma of patients treated with this drug. The inhibition was voltage-dependent, indicating an open-channel blocking mechanism. Furthermore, the inhibitory potency of atomoxetine did not vary when measured on NMDA receptors from different brain regions or with different subunit compositions.
  
  
  CONCLUSIONS
  The effective NMDA receptor antagonism by atomoxetine at low micromolar concentrations may be relevant to its clinical effects in the treatment of ADHD. Our data provide further evidence that altered glutamatergic transmission might play a role in ADHD pathophysiology.
authors.affiliation: Department of Child and Adolescent Psychiatry, University of Ulm, Germany. andrea.ludolph@uni-ulm.de <andrea.ludolph@uni-ulm.de>
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Ludolph
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Udvardi
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schaz
authors.forename: Carolin
authors.initials: C
authors.lastname: Henes
authors.forename: Oliver
authors.initials: O
authors.lastname: Adolph
authors.forename: Henry U
authors.initials: HU
authors.lastname: Weigt
authors.forename: Joerg M
authors.initials: JM
authors.lastname: Fegert
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Föhr
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000503:physiopathology; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011437:Propylamines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D011437:Propylamines; D016194:Receptors, N-Methyl-D-Aspartate; D000069445:Atomoxetine Hydrochloride