PMID- 16554746
OWN - NLM
STAT- MEDLINE
DCOM- 20061212
LR  - 20181201
IS  - 0893-133X (Print)
IS  - 0893-133X (Linking)
VI  - 31
IP  - 11
DP  - 2006 Nov
TI  - Clinically relevant doses of fluoxetine and reboxetine induce changes in the TrkB 
      content of central excitatory synapses.
PG  - 2415-23
AB  - We have studied the effect of low doses of two widely used antidepressants, 
      fluoxetine (Flx) and reboxetine (Rbx), on excitatory synapses of rat brain cortex 
      and hippocampus. After 15 days of Flx treatment (0.67 mg/kg/day), its plasma 
      level was 20.7+/-5.6 ng/ml. Analysis of postsynaptic densities (PSDs) by 
      immunoblotting revealed no changes in the glutamate receptor subunits GluR1, NR1, 
      NR2A/B, mGluR1alpha nor in the neurotrophin receptor p75(NTR). However, the 
      brain-derived neurotrophic factor (BDNF) receptor TrkB decreased by 42.8+/-6%, 
      and remained decreased after 6 weeks of treatment. The BDNF and TrkB content in 
      homogenates of cortex and hippocampus began to rise at 9 and 15 days, 
      respectively, and remained high for up to 6 weeks. Similar results were obtained 
      following chronic Rbx administration at 0.128 mg/kg/day. We propose that BDNF, 
      whose synthesis is increased by antidepressants, and which is in part released at 
      synaptic sites, binds to TrkB in PSDs, leading to the internalization of the 
      BDNF-TrkB complex and, thus, to a decrease of TrkB in the PSDs. This was 
      paralleled by greater levels of phosphorylated (ie activated) TrkB in the light 
      membrane fraction, that contains signaling endosomes. The retrograde transport of 
      endocyted BDNF/TrkB complexes from spines to cell bodies, where it activates the 
      synthesis of more BDNF, is a protracted process, potentially requiring several 
      cycles of TrkB/BDNF complex endocytosis and transport. This positive feedback 
      mechanism may help explain the time-lag between drug administration and its 
      therapeutic effect, that is, the antidepressant drug paradox.
FAU - Wyneken, Ursula
AU  - Wyneken U
AD  - Neuroscience Laboratory, Faculty of Medicine, Universidad de los Andes, Casilla, 
      Santiago, Chile.
FAU - Sandoval, Mauricio
AU  - Sandoval M
FAU - Sandoval, Soledad
AU  - Sandoval S
FAU - Jorquera, Franscisco
AU  - Jorquera F
FAU - Gonzalez, Ignacio
AU  - Gonzalez I
FAU - Vargas, Francisco
AU  - Vargas F
FAU - Falcon, Romina
AU  - Falcon R
FAU - Monari, Milena
AU  - Monari M
FAU - Orrego, Fernando
AU  - Orrego F
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060322
PL  - England
TA  - Neuropsychopharmacology
JT  - Neuropsychopharmacology : official publication of the American College of 
      Neuropsychopharmacology
JID - 8904907
RN  - 0 (Antidepressive Agents)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Morpholines)
RN  - 01K63SUP8D (Fluoxetine)
RN  - 21820-51-9 (Phosphotyrosine)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 947S0YZ36I (Reboxetine)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 3.6.5.2 (rab5 GTP-Binding Proteins)
SB  - IM
MH  - Animals
MH  - Antidepressive Agents/blood/*pharmacology
MH  - Blotting, Western/methods
MH  - Brain/cytology/*drug effects
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Fluoxetine/blood/*pharmacology
MH  - Glutamic Acid/metabolism
MH  - Immunoprecipitation/methods
MH  - Male
MH  - Morpholines/blood/*pharmacology
MH  - Phosphotyrosine/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reboxetine
MH  - Receptor, trkB/*metabolism
MH  - Subcellular Fractions/drug effects
MH  - Synapses/*drug effects
MH  - Time Factors
MH  - rab5 GTP-Binding Proteins/metabolism
EDAT- 2006/03/24 09:00
MHDA- 2006/12/13 09:00
CRDT- 2006/03/24 09:00
PHST- 2006/03/24 09:00 [pubmed]
PHST- 2006/12/13 09:00 [medline]
PHST- 2006/03/24 09:00 [entrez]
AID - 1301052 [pii]
AID - 10.1038/sj.npp.1301052 [doi]
PST - ppublish
SO  - Neuropsychopharmacology. 2006 Nov;31(11):2415-23. doi: 10.1038/sj.npp.1301052. 
      Epub 2006 Mar 22.