title: Dose-dependent modulation of apoptotic processes by fluoxetine in maturing neuronal cells: an in vitro study.
abstract: OBJECTIVE
  Recent studies indicate that the selective serotonin reuptake inhibitor (SSRI) fluoxetine is not solely effective by the instant inhibition of the serotonin transporter (SERT) but also by its influence on mitotic and/or apoptotic processes.
  
  
  METHODS
  To investigate the effects of the compound in vitro, we treated neurons from different brain areas with increasing concentrations of fluoxetine. Additionally, human embryonic kidney (HEK-293) cells and HEK-293 cells stably expressing the SERT were used. Cell viability was quantified by MTT-assay and apoptosis via fluorescence-activated cell-sorting analyses. Fluoxetine's effect on the γ-aminobutyric acid (GABA) receptor was electrophysiologically investigated to test the hypothesis if a GABA-mimetic effect exists that might lead - additionally to the well-known N-methyl-D-aspartate (NMDA)-antagonism - to increased apoptosis in immature neurons.
  
  
  RESULTS
  In hippocampal, cortical, and both types of HEK-293 cells, viability decreased and apoptosis increased in a dose-dependent manner (0.5-75 μM). In contrast, in mesencephalic and striatal cells the viability was unchanged or even slightly stimulated up to 20 μM fluoxetine. An anti-apoptotic effect of concentrations below 10 μM was observed in these cells. The GABA(A) receptor was directly activated by fluoxetine.
  
  
  CONCLUSIONS
  We conclude that fluoxetine affects apoptotic processes independently from SERT expression. Since especially the combined GABA-mimetic and NMDA-antagonistic effects increase apoptosis in developing neuronal cells, whereas both effects are neuroprotective in adult neurons we hypothesise that these mechanisms explain the discrepancy of in vitro and in vivo studies.
authors.affiliation: Institute of Anatomy and Cell Biology, University of Ulm, Ulm, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schaz
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Föhr
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebau
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
authors.forename: Michael
authors.initials: M
authors.lastname: Koelch
authors.forename: Joerg M
authors.initials: JM
authors.lastname: Fegert
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Ludolph
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005473:Fluoxetine / Q000378:metabolism / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D016202:N-Methylaspartate / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D005473:Fluoxetine; D016202:N-Methylaspartate; D018079:Receptors, GABA; D017367:Selective Serotonin Reuptake Inhibitors