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 20.7+/-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.
Subject(s)
Antidepressive Agents/pharmacology , Brain/drug effects , Fluoxetine/pharmacology , Morpholines/pharmacology , Receptor, trkB/metabolism , Synapses/drug effects , Animals , Antidepressive Agents/blood , Blotting, Western/methods , Brain/cytology , Brain-Derived Neurotrophic Factor/metabolism , Dose-Response Relationship, Drug , Fluoxetine/blood , Glutamic Acid/metabolism , Immunoprecipitation/methods , Male , Morpholines/blood , Phosphotyrosine/metabolism , Rats , Rats, Sprague-Dawley , Reboxetine , Subcellular Fractions/drug effects , Time Factors , rab5 GTP-Binding Proteins/metabolismABSTRACT
En 20 de 35 casos de tumor del sistema nervioso central se pudo demostrar la presencia de células neoplásicas en el LCR mediante la técnica de sedimentación espontánea de Sayk modificada. Este porcentaje de resultados positivos (57%) es sensiblemente similar o superior a aquellos que han sido reportados por otros autores. Catorce casos corresponden a neoplasias malignas (6 metastásicas y 8 primarias) y 6 a neoplasias benignas primarias. Se destaca la importancia diagnóstica del hallazgo accidental de células neoplásicas en el LCR en casos en los que no hay sospecha clínica previa de afección tumoral del neuroeje, lo que ocurre com mayor frecuencia en pacientes con carcinomatosis meníngea
