Inhibitory effects of antidepressant fluoxetine on cloned Kv2.1 potassium channel expressed in HEK293 cells

Wang, Weiping; Yin, Huajing; Feng, Nan; Wang, Xiaoliang

doi:10.1016/j.ejphar.2020.173097

Cited by 12 publications

(10 citation statements)

References 33 publications

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“…The mechanism of this effect is not known. It should be noted that some SSRIs including fluoxetine may modulate several aspects of brain neurochemistry in a serotonin-independent manner, e.g., via inhibition of cellular Wnt signalling [ 47 ] and voltage-gated potassium channels closing [ 48 ]. Interestingly, only acute but not chronic fluoxetine administration affects inhibitory synapse formation [ 49 ] while extended SSRI treatment has been shown to upregulate adult neurogenesis and neuroplasticity through increased brain-derived neurotrophic factor (BDNF) signalling [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of Escitalopram on the Number of DCX-Positive Cells and NMUR2 Receptor Expression in the Rat Hippocampus under the Condition of NPSR Receptor Blockade

et al. 2022

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Background: Neuropeptide S (NPS) is a multifunctional regulatory factor that exhibits a potent anxiolytic activity in animal models. However, there are no reports dealing with the potential molecular interactions between the activity of selective serotonin reuptake inhibitors (SSRIs) and NPS signaling, especially in the context of adult neurogenesis and the expression of noncanonical stress-related neuropeptides such as neuromedin U (NMU). The present work therefore focused on immunoexpression of neuromedin U receptor 2 (NMUR2) and doublecortin (DCX) in the rat hippocampus after acute treatment with escitalopram and in combination with selective neuropeptide S receptor (NPSR) blockade. Methods: Studies were carried out on adult, male Sprague-Dawley rats that were divided into five groups: animals injected with saline (control) and experimental individuals treated with escitalopram (at single dose 10 mg/kg daily), escitalopram + SHA-68, a selective NPSR antagonist (at single dose 40 mg/kg), SHA-68 alone, and corresponding vehicle control. All animals were sacrificed under halothane anaesthesia. The whole hippocampi were quickly excised, fixed, and finally sliced for general qualitative immunohistochemical assessment of the NPSR and NMUR2 expression. The number of immature neurons was enumerated using immunofluorescent detection of doublecortin (DCX) expression within the subgranular zone (SGZ). Results: Acute escitalopram administration affects the number of DCX and NMUR2-expressing cells in the adult rat hippocampus. A decreased number of DCX-expressing neuroblasts after treatment with escitalopram was augmented by SHA-68 coadministration. Conclusions: Early pharmacological effects of escitalopram may be at least partly connected with local NPSR-related alterations of neuroblast maturation in the rat hippocampus. Escitalopram may affect neuropeptide and DCX-expression starting even from the first dose. Adult neurogenesis may be regulated via paracrine neuropeptide S and NMU-related signaling.

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Section: Discussionmentioning

confidence: 99%

Effect of Escitalopram on the Number of DCX-Positive Cells and NMUR2 Receptor Expression in the Rat Hippocampus under the Condition of NPSR Receptor Blockade

et al. 2022

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“…This increase in serotonin leads to increased activation of serotonin receptors. However, fluoxetine also regulates neural physiology independent of serotonin, by inhibiting Wnt [ 28 ] and the potassium channel, Kv2.1 [ 27 ]. Similar to what is observed in autism, fluoxetine has previously been shown to increase dendritic spine formation [ 14 , 15 , 16 , 17 ].To test the hypothesis that fluoxetine alters fetal synapse formation, we developed human cortical spheroids that recapitulate the second trimester fetal brain, when synapses form [ 3 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, increasing evidence suggests that SSRIs such as fluoxetine can alter neurodevelopment independent of serotonin. For example, fluoxetine inhibits voltage-gated potassium channels in non-neuronal human embryonic kidney (HEK) cells expressing Kv2.1 [ 27 ]. Additionally, fluoxetine, but not other SSRIs, alters morphogenesis in a mouse embryoid body model through inhibition of Wnt signaling [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

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

Tate

Kirk

Tseng

et al. 2021

IJMS

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The developing prenatal brain is particularly susceptible to environmental disturbances. During prenatal brain development, synapses form between neurons, resulting in neural circuits that support complex cognitive functions. In utero exposure to environmental factors such as pharmaceuticals that alter the process of synapse formation increases the risk of neurodevelopmental abnormalities. However, there is a lack of research into how specific environmental factors directly impact the developing neural circuitry of the human brain. For example, selective serotonin reuptake inhibitors are commonly used throughout pregnancy to treat depression, yet their impact on the developing fetal brain remains unclear. Recently, human brain models have provided unprecedented access to the critical window of prenatal brain development. In the present study, we used human neurons and cortical spheroids to determine whether the selective serotonin reuptake inhibitor fluoxetine alters neurite and synapse formation and the development of spontaneous activity within neural circuits. We demonstrate that cortical spheroids express serotonin transporter, thus recapitulating the early developmental expression of serotonin transporter associated with cortical pyramidal neurons. Cortical spheroids also appropriately express serotonin receptors, such as synaptic 5-HT2A and glial 5-HT5A. To determine whether fluoxetine can affect developing neural circuits independent of serotonergic innervation from the dorsal and medial raphe nuclei, we treated cortical neurons and spheroids with fluoxetine. Fluoxetine alters neurite formation in a dose-dependent fashion. Intriguingly, in cortical spheroids, neither acute nor chronic fluoxetine significantly altered excitatory synapse formation. However, only acute, but not chronic fluoxetine exposure altered inhibitory synaptogenesis. Finally, fluoxetine reversibly suppresses neuronal activity in a dose-dependent manner. These results demonstrate that fluoxetine can acutely alter synaptic function in developing neural circuits, but the effects were not long-lasting. This work provides a foundation for future studies to combine serotonergic innervation with cortical spheroids and assess the contributions of fluoxetine-induced alterations in serotonin levels to brain development.

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“…Their therapeutic effect is mainly attributed to blocking the reuptake transporter of monoamines, followed by an extraneuronal increase of 5‐HT in various parts of the brain (Zhou et al, 2009). However, a growing number of studies provide evidence about other non‐monoaminergic‐related mechanisms, including the modulation of electrogenic ion channels (Wang et al, 2020), perturbation of calcium signalisation (Chang et al, 2017) or neuropeptides alterations (Gołyszny & Obuchowicz, 2019).…”

Section: Introductionmentioning

confidence: 99%

Effects of prenatal exposure to fluoxetine on circadian rhythmicity in the locomotor activity and neuropeptide Y and 5‐HT expression in male and female adult Wistar rats

Linhares

Meurer

Aquino

et al. 2022

Intl J of Devlp Neuroscience

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Serotonin (5-HT) reuptake inhibitors, such as fluoxetine, are the most prescribed antidepressant for maternal depression. In this sense, it exposes mothers and the brains of infants to increased modulatory and trophic effects of serotonergic neurotransmission. 5-HT promotes essential brain changes throughout its development, which include neuron migration, differentiation and organisation of neural circuitries related to emotional, cognitive and circadian behavior. Early exposure to the SSRIs induces long-term effects on behavioral and neural serotonergic signalisation. We have aimed to evaluate the circadian rhythm of locomotor activity and the neurochemical content, neuropeptide Y (NPY) and 5-HT in three brain areas: intergeniculate leaflet (IGL), suprachiasmatic nuclei (SCN) and raphe nuclei (RN), at two zeitgebers (ZT6 and ZT18), in male and female rat's offspring early exposed (developmental period GD13-GD21) to fluoxetine (20 mg/kg). First, we have conducted daily records of the locomotor activity rhythm using activity sensors coupled to individual cages over 4 weeks. We have lastly evaluated the immunoreactivity of NPY in both SCN and IGL, as well the 5-HT expression in the dorsal and medial RN. In summary, our results showed that (1) prenatal fluoxetine affects phase entrainment of the rest/activity rhythm at ZT6 and ZT18, more in male than female specimens, and (2) modulates the NPY and 5-HT expression. Here, we show male rats are more susceptible to phase entrainment and the NPY and 5-HT misexpression compared to female ones. The sex differences induced by early exposure to fluoxetine in both the circadian rhythm of locomotor activity and the neurochemical expression into SCN, IGL and midbrain

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Inhibitory effects of antidepressant fluoxetine on cloned Kv2.1 potassium channel expressed in HEK293 cells

Cited by 12 publications

References 33 publications

Effect of Escitalopram on the Number of DCX-Positive Cells and NMUR2 Receptor Expression in the Rat Hippocampus under the Condition of NPSR Receptor Blockade

Effect of Escitalopram on the Number of DCX-Positive Cells and NMUR2 Receptor Expression in the Rat Hippocampus under the Condition of NPSR Receptor Blockade

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

Effects of prenatal exposure to fluoxetine on circadian rhythmicity in the locomotor activity and neuropeptide Y and 5‐HT expression in male and female adult Wistar rats

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