TY - JOUR T1 - Long-Term Duloxetine Treatment Normalizes Altered Brain-Derived Neurotrophic Factor Expression in Serotonin Transporter Knockout Rats through the Modulation of Specific Neurotrophin Isoforms JF - Molecular Pharmacology JO - Mol Pharmacol SP - 846 LP - 853 DO - 10.1124/mol.109.063081 VL - 77 IS - 5 AU - Francesca Calabrese AU - Raffaella Molteni AU - Annamaria Cattaneo AU - Flavia Macchi AU - Giorgio Racagni AU - Massimo Gennarelli AU - Bart A. Ellenbroek AU - Marco A. Riva Y1 - 2010/05/01 UR - http://molpharm.aspetjournals.org/content/77/5/846.abstract N2 - Dysfunction of the serotonergic system is implicated in the etiology of many psychiatric disorders, including major depression. Major vulnerability genes for mood disorders are also related to the serotonergic system: one of these genes encodes for the serotonin transporter (SERT), which represent a major target for the action of antidepressant drugs. We have demonstrated recently that SERT knockout (KO) rats, generated by N-ethyl-N-nitrosourea-induced mutagenesis, show reduced expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex, suggesting that depression vulnerability can be associated with impaired neuronal plasticity. In the present study, we demonstrate that chronic treatment with the antidepressant duloxetine (DLX) was able to normalize the expression of BDNF mRNA-coding exon (IX) in the hippocampus and prefrontal cortex of SERT KO rats through the modulation of selected neurotrophin transcripts, whose expression was up-regulated by DLX only in SERT KO rats. On the other hand, the modulation of BDNF protein by DLX in frontal cortex was abolished in mutant rats. These data suggest that animals with a genetic defect of the serotonin transporter maintain the ability to show neuroplastic changes in response to antidepressant drugs. Because these animals show depression-like behavior, the region and isoform-specific increase of BDNF levels may be a mechanism activated by long-term antidepressant treatment to restore normal plasticity that is defective under genetic dysfunction of the serotonin transporter.Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics ER -