title: Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain--an in vivo study.
abstract: Attention-deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder. The norepinephrine transporter (NET) inhibitor atomoxetine, the first nonstimulant drug licensed for ADHD treatment, also acts as an N-methyl-D-aspartate receptor (NMDAR) antagonist. The compound's effects on gene expression and protein levels of NET and NMDAR subunits (1, 2A, and 2B) are unknown. Therefore, adolescent Sprague Dawley rats were treated with atomoxetine (3 mg/kg, intraperitoneal injection [i.p.]) or saline (0.9%, i.p.) for 21 consecutive days on postnatal days (PND) 21-41. In humans, atomoxetine's earliest clinical therapeutic effects emerge after 2-3 weeks. Material from prefrontal cortex, striatum (STR), mesencephalon (MES), and hippocampus (HC) was analyzed either directly after treatment (PND 42) or 2 months after termination of treatment (PND 101) to assess the compound's long-term effects. In rat brains analyzed immediately after treatment, protein analysis exhibited decreased levels of the NET in HC, and NMDAR subunit 2B in both STR and HC; the transcript levels were unaltered. In rat brains probed 2 months after final atomoxetine exposure, messenger RNA analysis also revealed significantly reduced levels of genes coding for NMDAR subunits in MES and STR. NMDAR protein levels were reduced in STR and HC. Furthermore, the levels of two SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, synaptophysin and synaptosomal-associated protein 25, were also significantly altered in both treatment groups. This in vivo study detected atomoxetine's effects beyond NET inhibition. Taken together, these data reveal that atomoxetine seems to decrease glutamatergic transmission in a brain region-specific manner. Long-term data show that the compound's impact is not due to an acute pharmacological effect but lasts or even amplifies after a drug-free period of 2 months, leading to altered development of synaptic composition. These alterations might contribute to atomoxetine's clinical effects in the treatment of ADHD, a neurodevelopmental disorder in which synaptic processes and especially a dysregulated glutamatergic metabolism seem to be involved.
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, University of Ulm, Ulm, Germany ; Institute of Anatomy and Cell Biology, University of Ulm, Ulm, Germany.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Udvardi
authors.affiliation: Department of Anaesthesiology, University of Ulm, Ulm, Germany.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Föhr
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, University of Ulm, Ulm, Germany ; Institute of Anatomy and Cell Biology, University of Ulm, Ulm, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Henes
authors.affiliation: Institute of Anatomy and Cell Biology, University of Ulm, Ulm, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebau
authors.affiliation: Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Dreyhaupt
authors.affiliation: Institute of Anatomy and Cell Biology, University of Ulm, Ulm, Germany.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychotherapy, University of Ulm, Ulm, Germany.
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Ludolph
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; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011437:Propylamines / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D018759:Adrenergic Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011437:Propylamines; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D000069445:Atomoxetine Hydrochloride
keywords: N-methyl-D-aspartate receptor; altered gene expression; atomoxetine; attention-deficit hyperactivity disorder (ADHD); in vivo study; neurodevelopment