1. ¹Center of Neuropharmacology, Department of Pharmacological Sciences, University of Milan, Milan, Italy
2. ²IRCCS San Giovanni di Dio-Fatebenefratelli, Brescia, Italy
3. ³Division of Biology and Genetic, Department of Biomedics and Biotechnologies Sciences, University of Brescia, Brescia, Italy
4. ⁴Medical Department Eli Lilly Italia SpA, Sesto Fiorentino, Italy

Correspondence: Professor MA Riva, Center of Neuropharmacology, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, Milan 20133, Italy. Tel: +39 02 5031 8334; Fax: +39 02 5031 8278; E-mail: M.Riva@unimi.it

⁵These authors contributed equally to this study.

Received 28 July 2008; Revised 2 October 2008; Accepted 21 October 2008; Published online 19 November 2008.

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.