PMID- 24348020
OWN - NLM
STAT- MEDLINE
DCOM- 20140829
LR  - 20211021
IS  - 1177-8881 (Electronic)
IS  - 1177-8881 (Linking)
VI  - 7
DP  - 2013
TI  - Atomoxetine affects transcription/translation of the NMDA receptor and the 
      norepinephrine transporter in the rat brain--an in vivo study.
PG  - 1433-46
LID - 10.2147/DDDT.S50448 [doi]
AB  - 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.
FAU - Udvardi, Patrick T
AU  - Udvardi PT
AD  - Department of Child and Adolescent Psychiatry and Psychotherapy, University of 
      Ulm, Ulm, Germany ; Institute of Anatomy and Cell Biology, University of Ulm, 
      Ulm, Germany.
FAU - Fohr, Karl J
AU  - Fohr KJ
AD  - Department of Anaesthesiology, University of Ulm, Ulm, Germany.
FAU - Henes, Carolin
AU  - Henes C
AD  - Department of Child and Adolescent Psychiatry and Psychotherapy, University of 
      Ulm, Ulm, Germany ; Institute of Anatomy and Cell Biology, University of Ulm, 
      Ulm, Germany.
FAU - Liebau, Stefan
AU  - Liebau S
AD  - Institute of Anatomy and Cell Biology, University of Ulm, Ulm, Germany.
FAU - Dreyhaupt, Jens
AU  - Dreyhaupt J
AD  - Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.
FAU - Boeckers, Tobias M
AU  - Boeckers TM
AD  - Institute of Anatomy and Cell Biology, University of Ulm, Ulm, Germany.
FAU - Ludolph, Andrea G
AU  - Ludolph AG
AD  - Department of Child and Adolescent Psychiatry and Psychotherapy, University of 
      Ulm, Ulm, Germany.
LA  - eng
PT  - Journal Article
DEP - 20131204
PL  - New Zealand
TA  - Drug Des Devel Ther
JT  - Drug design, development and therapy
JID - 101475745
RN  - 0 (Adrenergic Uptake Inhibitors)
RN  - 0 (Norepinephrine Plasma Membrane Transport Proteins)
RN  - 0 (Propylamines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 57WVB6I2W0 (Atomoxetine Hydrochloride)
SB  - IM
MH  - Adrenergic Uptake Inhibitors/administration & dosage/*pharmacology
MH  - Animals
MH  - Atomoxetine Hydrochloride
MH  - Attention Deficit Disorder with Hyperactivity/drug therapy/physiopathology
MH  - Brain/drug effects/metabolism
MH  - Gene Expression Regulation/drug effects
MH  - Glutamic Acid/metabolism
MH  - Injections, Intraperitoneal
MH  - Male
MH  - Norepinephrine Plasma Membrane Transport Proteins/*drug 
      effects/genetics/metabolism
MH  - Propylamines/administration & dosage/*pharmacology
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, N-Methyl-D-Aspartate/*drug effects/genetics/metabolism
MH  - Species Specificity
MH  - Time Factors
MH  - Transcription, Genetic/drug effects
PMC - PMC3857115
OTO - NOTNLM
OT  - N-methyl-D-aspartate receptor
OT  - altered gene expression
OT  - atomoxetine
OT  - attention-deficit hyperactivity disorder (ADHD)
OT  - in vivo study
OT  - neurodevelopment
EDAT- 2013/12/19 06:00
MHDA- 2014/08/30 06:00
PMCR- 2013/12/04
CRDT- 2013/12/19 06:00
PHST- 2013/12/19 06:00 [entrez]
PHST- 2013/12/19 06:00 [pubmed]
PHST- 2014/08/30 06:00 [medline]
PHST- 2013/12/04 00:00 [pmc-release]
AID - dddt-7-1433 [pii]
AID - 10.2147/DDDT.S50448 [doi]
PST - epublish
SO  - Drug Des Devel Ther. 2013 Dec 4;7:1433-46. doi: 10.2147/DDDT.S50448. eCollection 
      2013.