Long-Term Duloxetine Treatment Normalizes Altered Brain-Derived Neurotrophic Factor Expression in Serotonin Transporter Knockout Rats through the Modulation of Specific Neurotrophin Isoforms

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 isoformspecific 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.Major depression is believed to originate from the interaction between susceptibility genes and environmental events. Genetic susceptibility may be due, at least in part, to deficits in neuronal resiliency and neuroprotective responses or, alternatively, to exacerbated function of systems that may lead to neuronal dysfunction and psychopathology (Duman, 2009). There is mounting evidence suggesting that heightened susceptibility in mood disorders can be due to impaired neuronal plasticity, driven by reduced expression and function of key mediators, such as the neurotrophin brain-derived neurotrophic factor (BDNF), which are important for cellular resilience (Tsankova et al., 2006;McClung and Nestler, 2008;Pittenger and Duman, 2008;Calabrese et al., 2009). Moreover, the modulation of BDNF represents a crucial step in long-term adaptive changes brought about by antidepressant drugs (Calabrese et al., 2007Castrén et al., 2007;Kozisek et al., 2008;Molteni et al., 2009). Although there is a general agreement that antidepressant drug treatment can modulate the expression of BDNF, controversies exist with regard to the magnitude, timing, and anatomical specificity of such changes Groves, 2007;Martinowich et al., 2007;Kozisek et al., 2008; ABBREVIATIONS: SERT, serotonin transporter; KO, knockout; WT, wild type; BDNF, brain-derived neurotrophic factor; DLX, duloxetine; PCR, polymerase chain reaction; ANOVA, analysis of variance; SCPHT, single-contrast ...

Treatment-resistant depression: are animal models of depression fit for purpose?

“…To our knowledge, the behavioural effects of chronic SSRIs have not been assessed after genetic deletion of the serotonin transporter. However, the effects of chronic duloxetine, a mixed 5-HT-NA uptake inhibitor, on brain-derived neurotrophic factor (BDNF) levels in the hippocampus and the frontal cortex were maintained in this model (Calabrese et al 2010), suggesting that antidepressant resistance may be specific to SSRIs.…”

Exaggerated Increases in Microglia Proliferation, Brain Inflammatory Response and Sickness Behaviour upon Lipopolysaccharide Stimulation in Non-Obese Diabetic Mice

“…BDNF is a well-known growth factor for neuronal cells and a deficiency of BDNF has been suggested as an important factor in the development of mood disorders in both preclinical [51,52,53] and clinical [54] reports. Moreover, a decrease in the level of BDNF in the brain due to inflammatory stimulation is a well-known phenomenon, with IL-1β [55] and LPS [31,56] previously reported as reducing BDNF expression in the rodent brain.…”

The preclinical profile of lurasidone: clinical relevance for the treatment of schizophrenia

“…We used rats lacking the serotonin transporter (SERT-KO), which can mimic the human dysfunction of SERT gene that has been associated with enhanced susceptibility to mood disorders [64]. SERT-KO rats displayed anxiety and depressive behaviors, which were associated with a significant reduction of BDNF expression [65][66][67]. Chronic treatment with lurasidone was able to normalize the reduced expression of the neurotrophin BDNF in the prefrontal cortex of SERT-KO rats, an effect that occurred through the regulation of specific neurotrophin transcripts (primarily exon VI).…”