Long-term duloxetine treatment normalizes altered brain-derived neurotrophic factor expression in serotonin transporter knockout rats through the modulation of specific neurotrophin isoforms

Francesca Calabrese, Raffaella Molteni, Annamaria Cattaneo, Flavia Macchi, Giorgio Racagni, Massimo Gennarelli, Bart A. Ellenbroek, Marco A. Riva

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
Pages (from-to)846-853
Number of pages8
JournalMolecular Pharmacology
Volume77
Issue number5
DOIs
Publication statusPublished - May 2010

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Serotonin Plasma Membrane Transport Proteins
Brain-Derived Neurotrophic Factor
Nerve Growth Factors
Protein Isoforms
Antidepressive Agents
Depression
Prefrontal Cortex
Hippocampus
Ethylnitrosourea
Neuronal Plasticity
Aptitude
Frontal Lobe
Mood Disorders
Mutagenesis
Genes
Psychiatry
Duloxetine Hydrochloride
Exons
Messenger RNA

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

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Long-term duloxetine treatment normalizes altered brain-derived neurotrophic factor expression in serotonin transporter knockout rats through the modulation of specific neurotrophin isoforms. / Calabrese, Francesca; Molteni, Raffaella; Cattaneo, Annamaria; Macchi, Flavia; Racagni, Giorgio; Gennarelli, Massimo; Ellenbroek, Bart A.; Riva, Marco A.

In: Molecular Pharmacology, Vol. 77, No. 5, 05.2010, p. 846-853.

Research output: Contribution to journalArticle

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