title: Fluoxetine suppresses synaptically induced [Ca²⁺]i spikes and excitotoxicity in cultured rat hippocampal neurons.
abstract: Fluoxetine is a widely used antidepressant with an action that is primarily attributed to the inhibition of serotonin re-uptake into the synaptic terminals of the central nervous system. Fluoxetine also has blocking effects on various ion channels, including Ca(2+) channels. It remains unclear, however, how fluoxetine may affect synaptically induced [Ca(2+)](i) spikes. We investigated the effects of fluoxetine on [Ca(2+)](i) spikes, along with the subsequent neurotoxicity that is synaptically evoked by lowering extracellular Mg(2+) in cultured rat hippocampal neurons. Fluoxetine inhibited the synaptically induced [Ca(2+)](i) spikes in p-chloroamphetamine-treated and non-treated neurons, in a concentration-dependent manner. However, other selective serotonin reuptake inhibitors, such as paroxetine and citalopram, did not significantly affect the spikes. Pretreatment with fluoxetine for 5 min inhibited [Ca(2+)](i) increases induced by glutamate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and N-methyl-d-aspartate. Fluoxetine also inhibited α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced currents. In addition, fluoxetine decreased the [Ca(2+)](i) responses induced by the metabotrophic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine or the ryanodine receptor agonist caffeine. Fluoxetine inhibited [Ca(2+)](i) responses induced by 20mM KCl. Fluoxetine decreased the release of FM1-43 induced by electric field stimulation. Furthermore, fluoxetine inhibited 0.1mM [Mg(2+)](o)-induced cell death. Collectively, our results suggest that fluoxetine suppresses the spikes and protects neurons against excitotoxicity, particularly in cultured rat hippocampal neurons, presumably due to both direct inhibition of presynaptic glutamate release and postsynaptic glutamate receptor-mediated [Ca(2+)](i) signaling. In addition to an indirect inhibitory effect via 5-HT levels, these data suggest a new, possibly direct inhibitory action of fluoxetine on synaptically induced [Ca(2+)](i) spikes and neuronal cell death.
authors.affiliation: Department of Physiology, College of Medicine, Dankook University, San #29, Anseo-dong, Dongnam-gu, Cheonan, Chungnam 330-714, South Korea.
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Tae Hyeong
authors.initials: TH
authors.lastname: Kim
authors.forename: Se Joon
authors.initials: SJ
authors.lastname: Choi
authors.forename: Yi Jae
authors.initials: YJ
authors.lastname: Hong
authors.forename: Ji Seon
authors.initials: JS
authors.lastname: Yang
authors.forename: Ki-Wug
authors.initials: KW
authors.lastname: Sung
authors.forename: Duck-Joo
authors.initials: DJ
authors.lastname: Rhie
authors.forename: Sang June
authors.initials: SJ
authors.lastname: Hahn
authors.forename: Shin Hee
authors.initials: SH
authors.lastname: Yoon
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D015283:Citalopram / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology* / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D008275:Magnesium Deficiency / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism; D017374:Paroxetine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists; D018490:Serotonin Agents / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D013569:Synapses / Q000187:drug effects; D010133:p-Chloroamphetamine / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D015283:Citalopram; D018690:Excitatory Amino Acid Agonists; D005473:Fluoxetine; D018696:Neuroprotective Agents; D018377:Neurotransmitter Agents; D017374:Paroxetine; D018094:Receptors, Metabotropic Glutamate; D018490:Serotonin Agents; D017367:Selective Serotonin Reuptake Inhibitors; D010133:p-Chloroamphetamine