title: New insights into the acute actions from a high dosage of fluoxetine on neuronal and cardiac function: Drosophila, crayfish and rodent models.
abstract: The commonly used mood altering drug fluoxetine (Prozac) in humans has a low occurrence in reports of harmful effects from overdose; however, individuals with altered metabolism of the drug and accidental overdose have led to critical conditions and even death. We addressed direct actions of high concentrations on synaptic transmission at neuromuscular junctions (NMJs), neural properties, and cardiac function unrelated to fluoxetine's action as a selective 5-HT reuptake inhibitor. There appears to be action in blocking action potentials in crayfish axons, enhanced occurrences of spontaneous synaptic vesicle fusion events in the presynaptic terminals at NMJs of both Drosophila and crayfish. In rodent neurons, cytoplasmic Ca(2+) rises by fluoxetine and is thapsigargin dependent. The Drosophila larval heart showed a dose dependent effect in cardiac arrest. Acute paralytic behavior in crayfish occurred at a systemic concentration of 2mM. A high percentage of death as well as slowed development occurred in Drosophila larvae consuming food containing 100μM fluoxetine. The release of Ca(2+) from the endoplasmic reticulum in neurons and the cardiac tissue as well as blockage of voltage-gated Na(+) channels in neurons could explain the effects on the whole animal as well as the isolated tissues. The use of various animal models in demonstrating the potential mechanisms for the toxic effects with high doses of fluoxetine maybe beneficial for acute treatments in humans. Future studies in determining how fluoxetine is internalized in cells and if there are subtle effects of these mentioned mechanisms presented with chronic therapeutic doses are of general interest.
authors.affiliation: Department of Biology, University of Kentucky, USA; Lexington, KY, USA; Department of Biology, University of Salahaddin, Erbil, Iraq.
authors.forename: Zana R
authors.initials: ZR
authors.lastname: Majeed
authors.affiliation: Department of Biology, University of Kentucky, USA; Lexington, KY, USA; Centre College, Danville, KY, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Ritter
authors.affiliation: Department of Biology, University of Kentucky, USA; Lexington, KY, USA; Morehead State University, Morehead, KY, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Robinson
authors.affiliation: Department of Biology, University of Kentucky, USA; Lexington, KY, USA; V.M.F., University of Leipzig, Leipzig, Germany.
authors.forename: Sandra L E
authors.initials: SL
authors.lastname: Blümich
authors.affiliation: Temple University, Philadelphia, PA, USA.
authors.forename: Eugen
authors.initials: E
authors.lastname: Brailoiu
authors.affiliation: Department of Biology, University of Kentucky, USA; Lexington, KY, USA. Electronic address: RLCOOP1@uky.edu.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Cooper
mesh_terms: D000818:Animals; D003400:Astacoidea / Q000187:drug effects* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005473:Fluoxetine / Q000633:toxicity*; D006323:Heart Arrest / Q000139:chemically induced / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D018570:Risk Assessment; D017367:Selective Serotonin Reuptake Inhibitors / Q000633:toxicity*; D013045:Species Specificity; D013997:Time Factors
chemical_list: D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Heart; Invertebrate; Neuromuscular junction; Serotonin; Synapse