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

Abstract

Compelling evidence suggests that mood disorders are characterized by reduced neuronal plasticity that might be normalized by pharmacological intervention. Our study aimed to establish whether chronic antidepressant treatment could alter the modulation of the neurotrophin brain-derived neurotrophic factor (BDNF) under a stressful condition. Therefore, adult male Sprague-Dawley rats were treated for 21 days with vehicle or with the SNRI duloxetine and, 24 h after the last injection, exposed to an acute swim stress (5 min) before being killed 15 min later. We found that chronic duloxetine treatment was able to modulate the rapid transcriptional changes of BDNF isoforms produced by an acute swim stress. Indeed whereas the mRNA levels of BDNF exon IV were upregulated by stress in vehicle as well as in duloxetine-treated rats, a significant increase of exon VI and exon IX was only found in rats that were pretreated with the antidepressant. These differential effects are in part because of selective changes in signaling pathways involved in the control of BDNF transcription. Moreover, the acute stressful episode significantly increased the levels of mature BDNF protein in the synaptosomal compartment in rats that were pretreated with the antidepressant, but not in control animals. Our results suggest that chronic antidepressant treatment might affect the responsiveness of BDNF under stressful conditions, suggesting that pharmacological intervention could 'prime' neuroprotective pathways and render them more responsive to preserve cell function and viability.

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.…”

A Comparison of Resveratrol and Vitamin C Therapy on Expression of BDNF in Stressed Rat Brain Homogenate

“…This result is consistent with few of the earlier studies [25][26][27], however a study by Tagliari et al, [28] claim that various chronic stress models used in rats has not affected BDNF expression in the hippocampus. Although the exact mechanism by which prolonged stressful experiences regulating BDNF is still unknown, the involvement of hormonal and neurotransmitter systems, has to be taken into consideration [29,30].…”