Fluoxetine Suppresses Glutamate- and GABA-Mediated Neurotransmission by Altering SNARE Complex.

Vesna Lazarevic,Per Svenningsson,Ioannis Mantas,Ivana Flais

doi:10.3390/ijms20174247

Vesna Lazarevic, Per Svenningsson + Show 2 more

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https://doi.org/10.3390/ijms20174247

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Abstract

Major depressive disorder is one of the most common neuropsychiatric disorders worldwide. The treatment of choice that shows good efficacy in mood stabilization is based on selective serotonin reuptake inhibitors (SSRIs). Their primary mechanism of action is considered to be the increased synaptic concentration of serotonin through blockade of the serotonin transporter (SERT). In this study, we described an alternative mode of action of fluoxetine (FLX), which is a representative member of the SSRI class of antidepressants. We observed that FLX robustly decreases both glutamatergic and gamma-Aminobutyric acid (GABA)-ergic synaptic release in a SERT-independent manner. Moreover, we showed that this effect may stem from the ability of FLX to change the levels of main components of the SNARE (solubile N-ethylmaleimide-sensitive factor attachment protein receptor) complex. Our data suggest that this downregulation of SNARE fusion machinery involves diminished activity of protein kinase C (PKC) due to FLX-induced blockade of P/Q type of voltage-gated calcium channels (VGCCs). Taken together, by virtue of its inhibition at SERT, fluoxetine increases extracellular serotonin levels; however, at the same time, by reducing SNARE complex function, this antidepressant reduces glutamate and GABA release.

Highlights

Major depressive disorder (MDD) is one of the most common diseases in the world
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Tryptophan hydroxylase 2 (TPH2) is the enzyme responsible for the production of brain-derived serotonin and is mostly expressed by neurons located in brainstem raphe nuclei [10]

Summary

Introduction

Major depressive disorder (MDD) is one of the most common diseases in the world. MDD diagnosis is based on at least one episode of depressed mood, lack of motivation, cognitive dysfunction, and autonomic disturbances; the exact pathophysiological aspects of the disease remain largely unknown. Depressive mood traits and MDD are frequent comorbidities of neurodegenerative disorders, especially Parkinson’s disease (PD) [7,8]. Selective serotonin reuptake inhibitors (SSRI) are considered as antidepressants with high combined efficacy and tolerability [9]. For this reason, SSRIs are the most widely prescribed antidepressants in a lot of countries. Binding of SSRIs on SERT leads to the accumulation of serotonin in the synaptic cleft and subsequent greater occupation of serotonin receptors (5HTRs)

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