Chronic Duloxetine Treatment Induces Specific Changes in the Expression of BDNF Transcripts and in the Subcellular Localization of the Neurotrophin Protein

Abstract

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 serotoninnorepinephrine 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.

Developmental Influence of the Serotonin Transporter on the Expression of Npas4 and GABAergic Markers: Modulation by Antidepressant Treatment

“…We had previously demonstrated that chronic treatment with the SNRI antidepressant duloxetine is able to normalize Bdnf deficits in these animals, also through the modulation of Bdnf exon I and IV (Calabrese et al, 2010, present results). Such data are in agreement with the possibility that repeated, but not acute, treatment with major classes of antidepressants may improve neuronal plasticity through the modulation of Bdnf expression (Calabrese et al, 2007;Castren et al, 2007;Molteni et al, 2009a;Russo-Neustadt and Chen, 2005), and that this effect may contribute to their therapeutic action (Berton and Nestler, 2006;Calabrese et al, 2009;Calabrese et al, 2011;Groves, 2007;Martinowich et al, 2007).…”

Glucocorticoid Receptor and FKBP5 Expression Is Altered Following Exposure to Chronic Stress: Modulation by Antidepressant Treatment

“…While these changes restore the expression of FOXO1 reduced by CMS (see above), the increase in Gadd45b expression may be of interest considering that the gene is involved in DNA demethylation of several promoters including BDNF (Ma et al, 2009), which is important for neuroplasticity and antidepressant activity Schmidt et al, 2011). These results strengthen the link between the modulation of HPA axis activity and neuroadaptive mechanisms exerted by antidepressant drugs, although neuroprotective effects may be mediated and sustained by different mechanisms, since we have shown that the SNRI duloxetine may be more effective than fluoxetine in elevating BDNF expression (Calabrese et al, 2007Molteni et al, 2009;Shirayama et al, 2002), whereas chronic treatment with fluoxetine, but not duloxetine, exert significant effects on hippocampal neurogenesis (Marlatt et al, 2010).…”

“…Duloxetine is an SNRI widely used as antidepressant in human therapy (Frampton and Plosker, 2007). The dose selected in the present study is based on our previous work demonstrating the ability of chronic duloxetine treatment to effectively modulating neuronal plasticity (Calabrese et al, 2007;Molteni et al, 2009) as well as its normalizing properties in animals with genetic deletion of the serotonin transporter Guidotti et al, 2012). On day 43, in the morning, rats were killed by decapitation 24 h after the last duloxetine administration.…”

Acute Stress Responsiveness of the Neurotrophin BDNF in the Rat Hippocampus is Modulated by Chronic Treatment with the Antidepressant Duloxetine

“…One of these molecules is the neurotrophin brain-derived neurotrophic factor (BDNF), whose modulation represents a key step in long-term adaptive changes brought about by antidepressant drugs Groves, 2007;Martinowich et al, 2007;Tardito et al, 2006). The effects on BDNF are complex and may occur at several levels including transcription (Calabrese et al, 2007;Coppell et al, 2003;Kozisek et al, 2008;Molteni et al, 2006;Nair et al, 2007;Nibuya et al, 1995), translation and trafficking in specific subcellular compartments (Calabrese et al, 2007) as well as receptor activation and signaling Fumagalli et al, 2005;Saarelainen et al, 2003;Wyneken et al, 2006).…”