5-HTT independent effects of fluoxetine on neuroplasticity

Abstract

Selective serotonin reuptake inhibitors are among the most prescribed antidepressants. Fluoxetine is the lead molecule which exerts its therapeutic effects, at least in part, by promoting neuroplasticity through increased brain-derived neurotrophic factor (BDNF)/tropomyosin-related receptor kinase B (TrkB) signalling. It is unclear however, to which extent the neuroplastic effects of fluoxetine are solely mediated by the inhibition of the serotonin transporter (5-HTT). To answer this question, the effects of fluoxetine on neuroplasticity were analysed in both wild type (WT) and 5-Htt knock-out (KO) mice. Using Western blotting and RT-qPCR approaches, we showed that fluoxetine 10 µM activated BDNF/TrkB signalling pathways in both CD1 and C57BL/6J mouse primary cortical neurons. Interestingly, effects on BDNF signalling were observed in primary cortical neurons from both 5-Htt WT and KO mice. In addition, a 3-week in vivo fluoxetine treatment (15 mg/kg/d; i.p.) increased the expression of plasticity genes in brains of both 5-Htt WT and KO mice, and tended to equally enhance hippocampal cell proliferation in both genotypes, without reaching significance. Our results further suggest that fluoxetine-induced neuroplasticity does not solely depend on 5-HTT blockade, but might rely, at least in part, on 5-HTT-independent direct activation of TrkB.

Fluoxetine regulates eEF2 activity (phosphorylation) via HDAC1 inhibitory mechanism in an LPS-induced mouse model of depression

“…Later studies reveal that fluoxetine also exerts neuroprotective [ 41 ], anti-cancer [ 42 , 43 ], and anti-inflammatory effects [ 41 , 44 ]. Additional mechanistic results demonstrate that independent of serotonin level adjustment, and fluoxetine treatment promotes neuroplasticity via tropomyosin receptor kinase B (TrkB)/BDNF [ 45 ] and neurogenesis via glycogen synthase kinases (GSK-3β)/β-catenin signaling pathway [ 46 ], which may also contribute to its antidepressant effects. Although previous studies demonstrate HDAC activity involvement in anti-depression [ 29 , 47 ], and HDAC inhibition can re-boost the antidepressant effect of fluoxetine [ 48 , 49 ], the detailed link between specific HDAC subtypes and how it contributes to the antidepressant effects of fluoxetine are yet unknown.…”

Chronic fluoxetine treatment impairs motivation and reward learning by affecting neuronal plasticity in the central amygdala

“…On the other hand, fluoxetine treatment has been shown to induce neuronal plasticity and to alleviate impairments of certain types of learning, which can, at least partially, explain its therapeutic effects (Ampuero et al, 2019;Eavri et al, 2018;Levy et al, 2019;Maya Vetencourt et al, 2008;Ohira, Hagihara, Miwa, Nakamura, & Miyakawa, 2019;Rossi, 2016;Steinzeig, Cannarozzo, & Castrén, 2019;Sun et al, 2017). Markedly, some animal studies showed that the drug reverses anhedonia induced by stress as severe as that stemming from repeated social defeat and boosts performance in highly complex cognitive tasks performed with the use of automated behavioural assays (Gottschalk et al, 2018;Marwari & Dawe, 2018).…”

Effects of the Selective Serotonin Reuptake Inhibitor Fluoxetine on Developing Neural Circuits in a Model of the Human Fetal Cortex

“…When screening for pharmaceutical effects, it is important to consider multiple neurodevelopmental stages, as specific drugs may differentially impact distinct processes in the formation of neural circuits [ 30 ]. Notably, fluoxetine has been shown to upregulate neuroplasticity genes independent of serotonin [ 31 ] and to alter neurite outgrowth in non-serotonergic neural cell lines, mammalian primary neurons, and invertebrate neurons [ 32 , 33 ] similar to other selective serotonin reuptake inhibitors [ 34 ]. We therefore began by treating human neural progenitor cells with increasing doses of fluoxetine during the first 24 h of neural differentiation, as we have previously done to determine effects on early stages of neural differentiation and neurite extension [ 35 , 36 ].…”