title: Dual effects of fluoxetine on mouse early embryonic development.
abstract: Fluoxetine, a selective serotonin reuptake inhibitor, regulates a variety of physiological processes, such as cell proliferation and apoptosis, in mammalian cells. Little is known about the role of fluoxetine in early embryonic development. This study was undertaken to investigate the effect of fluoxetine during mouse early embryonic development. Late two-cell stage embryos (2-cells) were cultured in the presence of various concentrations of fluoxetine (1 to 50μM) for different durations. When late 2-cells were incubated with 5μM fluoxetine for 6h, the percentage that developed into blastocysts increased compared to the control value. However, late 2-cells exposed to fluoxetine (5μM) over 24h showed a reduction in blastocyst formation. The addition of fluoxetine (5μM) together with KN93 or KN62 (calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitors) failed to increase blastocyst formation. Fluoxetine treatment inhibited TREK-1 and TREK-2, members of the two-pore domain K(+) channel family expressed in mouse embryos, activities, indicating that fluoxetine-induced membrane depolarization in late 2-cells might have resulted from TREK inhibition. In addition, long-term exposure to fluoxetine altered the TREK mRNA expression levels. Furthermore, injection of siRNA targeting TREKs significantly decreased blastocyst formation by ~30% compared to injection of scrambled siRNA. Long-term exposure of fluoxetine had no effect on blastocyst formation of TREK deficient embryos. These results indicate that low-dose and short-term exposures of late 2-cells to fluoxetine probably increase blastocyst formation through activation of CaMKII-dependent signal transduction pathways, whereas long-term exposure decreases mouse early embryonic development through inhibition of TREK channel gating.
authors.affiliation: Department of Physiology and Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751, South Korea.
authors.forename: Chang-Woon
authors.initials: CW
authors.lastname: Kim
authors.forename: Changyong
authors.initials: C
authors.lastname: Choe
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Kim
authors.forename: Jae-Ik
authors.initials: JI
authors.lastname: Lee
authors.forename: Sook-Young
authors.initials: SY
authors.lastname: Yoon
authors.forename: Young-Woo
authors.initials: YW
authors.lastname: Cho
authors.forename: Sunkyu
authors.initials: S
authors.lastname: Han
authors.forename: Hyun-Min
authors.initials: HM
authors.lastname: Tak
authors.forename: Jaehee
authors.initials: J
authors.lastname: Han
authors.forename: Dawon
authors.initials: D
authors.lastname: Kang
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000187:drug effects; D015153:Blotting, Western; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002875:Chromosomes / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D010101:Oxygen Consumption / Q000187:drug effects; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005473:Fluoxetine; D024683:Potassium Channels, Tandem Pore Domain; D034741:RNA, Small Interfering; D017367:Selective Serotonin Reuptake Inhibitors; C503445:Kcnk10 protein, mouse; C103742:potassium channel protein TREK-1