New insights into the acute actions from a high dosage of fluoxetine on neuronal and cardiac function: Drosophila, crayfish and rodent models

Zana R. Majeed, Kyle Ritter, Jonathan Robinson, Sandra L.E. Blümich, Eugen Brailoiu, Robin L. Cooper

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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 Ca2+ 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 2 mM. A high percentage of death as well as slowed development occurred in Drosophila larvae consuming food containing 100 μM fluoxetine. The release of Ca2+ 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.

Original languageEnglish
Pages (from-to)52-61
Number of pages10
JournalComparative Biochemistry and Physiology Part - C: Toxicology and Pharmacology
StatePublished - Aug 12 2015

Bibliographical note

Funding Information:
KR and JR were supported by KY IDeA Network of Biomedical Research Excellence grant # P20GM103436 . ZRM supported by Higher Committee for Education Development (HCED) scholarship in Iraq. S.L.E.B. supported by Deutscher Akademischer Austausch Dienst (DAAD) German Academic Exchange Service . RISE—Program (Research Internships in Science and Engineering). Personal funds supplied by RLC . We greatly appreciate the suggestion and comments on this manuscript by Jeffrey R. Strawn, MD, FAACAP, Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati, OH, USA.

Publisher Copyright:
© 2015 Elsevier Inc.


  • Heart
  • Invertebrate
  • Neuromuscular junction
  • Serotonin
  • Synapse

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Toxicology
  • Cell Biology
  • Health, Toxicology and Mutagenesis


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