Long-Term duloxetine treatment normalizes altered brain-derived neurotrophic factor expression in serotonin transporter knockout rats through the modulation of specific neurotrophin isoforms.
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.
Center of Neuropharmacology, Department of Pharmacological Sciences, University of Milan, Milan, Italy.
Francesca
F
Calabrese
Raffaella
R
Molteni
Annamaria
A
Cattaneo
Flavia
F
Macchi
Giorgio
G
Racagni
Massimo
M
Gennarelli
Bart A
BA
Ellenbroek
Marco A
MA
Riva
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D000068736:Duloxetine Hydrochloride; D005625:Frontal Lobe / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D009414:Nerve Growth Factors / Q000502:physiology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D055647:Rats, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
D019208:Brain-Derived Neurotrophic Factor; D000068736:Duloxetine Hydrochloride; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes