Chronic duloxetine treatment induces specific changes in the expression of BDNF transcripts and in the subcellular localization of the neurotrophin protein.
There is growing evidence that brain-derived neurotrophic factor (BDNF) can be relevant to mood disorders and that modulation of its biosynthesis following prolonged antidepressant treatment may contribute to neuroplastic changes required for clinical response. In the present study, we investigated the effects of the novel antidepressant duloxetine on BDNF in the rat brain. Duloxetine is a serotonin-norepinephrine reuptake inhibitor that differs from other antidepressants by virtue of its balanced potency on both neurotransmitter systems. We found that chronic, but not acute, treatment with duloxetine produces a robust increase of exon V BDNF mRNA levels in frontal cortex when the animals were killed 1 or 24 h after the last administration. The expression of the neurotrophin was also increased in other cortical subregions, but not in the hippocampus. We also found that the increased expression of BDNF in frontal cortex was mainly sustained by enhanced mRNA levels for exons I and III, whereas the expression of exon IV was reduced. Protein analysis in different subcellular fractions showed that chronic treatment with duloxetine, but not with the prototypical SSRI fluoxetine, reduced mature BDNF in the cytosol, but markedly increased its levels in the crude synaptosomal fraction. Our data suggest that chronic treatment with the novel antidepressant duloxetine not only produces a marked upregulation of BDNF mRNA and protein, but may also affect the subcellular redistribution of the neurotrophin. These changes might improve synaptic plasticity and cognitive function that are defective in depressed subjects.
Calabrese
Francesca
F
Department of Pharmacological Sciences, Center of Neuropharmacology, University of Milan, Milan, Italy.
Molteni
Raffaella
R
Maj
Paola F
PF
Cattaneo
Annamaria
A
Gennarelli
Massimo
M
Racagni
Giorgio
G
Riva
Marco A
MA
D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D004334:Drug Administration Schedule; D000068736:Duloxetine Hydrochloride; D024202:Electrophoretic Mobility Shift Assay; D005091:Exons; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects / Q000648:ultrastructure*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013876:Thiophenes / Q000008:administration & dosage*; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D000068736:Duloxetine Hydrochloride; D012333:RNA, Messenger; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes