¹Neuroscience Laboratory, Faculty of Medicine, Universidad de los Andes, Casilla, Santiago, Chile

Correspondence: Dr F Orrego, Neuroscience Laboratory, Faculty of Medicine, Universidad de los Andes, Casilla 20106, Santiago 6782468, Chile. Tel: +562 412 9307; Fax: +562 214 1752; E-mail: forrego@uandes.cl

Received 17 June 2005; Revised 11 January 2006; Accepted 18 January 2006; Published online 22 March 2006.

Abstract

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 20.75.6 ng/ml. Analysis of postsynaptic densities (PSDs) by immunoblotting revealed no changes in the glutamate receptor subunits GluR1, NR1, NR2A/B, mGluR1 nor in the neurotrophin receptor p75^NTR. However, the brain-derived neurotrophic factor (BDNF) receptor TrkB decreased by 42.86%, 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.