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

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.

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“…Administration of fluoxetine in our study restored the levels of SE, NE, and DA, and moreover, it increased the level of Glu while the level of GABA was significantly reduced as compared to depressed group. These results agreed with those of Bymaster et al [23] and Lazarevic et al [24] who reported that in rat prefrontal cortex, acute systemic Values represent the mean% of five mice for each group (n = 10). @ p < 0.05: Statistically significant from normal control, *p < 0.05: Statistically significant from depressed group administration of fluoxetine produced a continuous elevation in NE and DA levels.…”

Jiedu Tongluo Granules Ameliorates Post-stroke Depression Rat Model via Regulating NMDAR/BDNF Signaling Pathway

“…Secondly, fluoxetine is a representative of SSRI antidepressants. Though fluoxetine could also treat glutamate toxicity in the hippocampus ( Ludka et al, 2017 ; Lazarevic et al, 2019 ), more detection of relative molecular will be better to increase the reliability of the results. Besides, we only explore the pharmacological effects of JDTLG on the glutamatergic system.…”

How Antidepressant Drugs Affect the Antielectroshock Action of Antiseizure Drugs in Mice: A Critical Review

“…For instance, fluoxetine decreased glutamate synaptic release. This effect can be explained by changes in the structure of the soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, the effector of vesicle docking, and fusion at presynaptic membranes [ 35 ]. The same mechanism seems to be involved in the action of chronically administered venlafaxine.…”