Differential BDNF Responses of Triple Versus Dual Reuptake Inhibition in Neuronal and Astrocytoma Cells as well as in Rat Hippocampus and Prefrontal Cortex

Abstract

Monoamine reuptake inhibitors increase brain-derived neurotrophic factor (BDNF) activity, and this growth factor is regarded as an interesting target for developing new antidepressant drugs. The aims of this study were to evaluate whether monoaminergic reuptake inhibition increases BDNF in vivo and in vitro as predicted by the neurotrophic hypothesis of depression, and whether triple reuptake inhibition has a superior BDNF response compared to dual reuptake inhibition. Twenty-one days of oral treatment (30 mg/kg) with the dual serotonin/noradrenaline reuptake inhibitor duloxetine or the triple serotonin/noradrenaline/dopamine reuptake inhibitor DOV 216,303 restored BDNF protein levels in the rat hippocampus, which were initially decreased due to injection stress. The prefrontal cortex contained increased BDNF levels only after DOV 216,303 treatment. In vitro, neither duloxetine nor DOV 216,303 altered intracellular BDNF levels in murine HT22 neuronal cells. In contrast, BDNF release was more effectively decreased following treatment with DOV 216,303 in these cells. In rat C62B astrocytomas, both antidepressants increased intracellular BDNF levels at their highest nontoxic concentration. C62B astrocytomas did not release BDNF, even after antidepressant treatment. Increased BDNF levels support the neurotrophic hypothesis of depression, but our findings do not clearly evidence that the BDNF response after triple reuptake inhibitors is more effective than after dual reuptake inhibitors. Moreover, the data suggest that the role of BDNF in neurons and astrocytes is complex and likely depends on factors including specificity of cell types in different brain regions, cell–cell interactions, and different mechanisms of action of antidepressants used.

BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities

“…30 Growing evidence suggests however that this cell type may also synthesize BDNF at functionally relevant levels under certain conditions such as neuronal lesion 17 or inflammation-like conditions. 31 Interestingly, it was recently proposed that astrocytes synthesize BDNF in vitro in response to SSRIs 20, 32 and 5-HT/norepinephrine or 5-HT/norepinephrine/dopamine reuptake inhibitors. 32 Such an event might have a significant role in the therapeutic activity of these classes of antidepressant drugs.…”

“…31 Interestingly, it was recently proposed that astrocytes synthesize BDNF in vitro in response to SSRIs 20, 32 and 5-HT/norepinephrine or 5-HT/norepinephrine/dopamine reuptake inhibitors. 32 Such an event might have a significant role in the therapeutic activity of these classes of antidepressant drugs. The present study used a novel and efficient BDNF-gene transfer strategy to shift the tropism of lentiviral vectors toward astrocytes to determine whether these cells may be activated by SSRIs to promote the in vivo synthesis/release of BDNF.…”

Brain-Derived Neurotrophic Factor, Depression, and Physical Activity: Making the Neuroplastic Connection

“…The synthesis of BDNF occurs in both the central and peripheral nervous system by target neurons under physiologic conditions and by astrocytes following injury, inflammation, or administration of antidepressants [ 30 – 32 ]. In the brain, neurons are considered a significant cellular source of BDNF, and synthesis occurs in regions that participate in emotional and cognitive function (e.g., hippocampus and frontal, parietal, and entorhinal areas).…”

The Monoaminergic Tripartite Synapse: A Putative Target for Currently Available Antidepressant Drugs

“…development of a new class of antidepressant drugs that simultaneously increase all the three monoamines [137]. The triple reuptake inhibitor DOV216303 has been recently shown to stimulate the synthesis of BDNF from hippocampal and cortical primary cultures of astrocytes [138], emphasizing a possible role of DA on glial cells to promote neurotrophic effects.…”

“…Together, these data strongly suggest that BDNF is predominantly synthesized by neurons [246], but reactive astrocytes could also produce this factor under particular conditions, such as in neurodegenerative diseases or after the exposure of cultured astrocytes to kainic acid [247,248]. Although the extremely low levels of BDNF in neurons have greatly complicated attempts to reliably localize this factor [249], the presence of SERT and 5-HT receptor subtypes on astrocytes, along with the recent observations that fluoxetine, imipramine, amitriptyline and TRIs upregulate BDNF in primary cultures of astrocytes [17,138,231], suggest that glial cells represent a permissive microenvironment for the production of new neurons and neuronal integration into existing functional networks in the dentate gyrus of the HP. To address the question of the in vivo contribution of astrocytic BDNF to antidepressant drug actions, we applied a new lentiviral strategy [250] aimed at overexpressing this neurotrophic factor in the hippocampal astrocytes of adult mice.…”