Title page Chronic duloxetine treatment normalizes altered BDNF expression in serotonin transporter knockout rats through the modulation of specific neurotrophin isoforms. Molecular Pharmacology Fast Forward. Running title page Running title: Duloxetine m

Abstract 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 recently demonstrated that SERT knockout (KO) rats, generated by ENU-induced mutagenesis, show reduced expression of the neurotrophin BDNF in 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. Conversely, the modulation of BDNF protein by DLX in frontal cortex was abolished in mutant rats. In summary, these data suggest that animals with a genetic defect of the serotonin transporter maintain the ability to show neuroplastic changes in response to AD drugs. Since these animals show depression-like behavior, the region and isoform-specific increase of BDNF levels may be a mechanism activated by chronic antidepressant treatment to restore normal plasticity that is defective under genetic dysfunction of the serotonin transporter