TY - JOUR
T1 - New insights into the acute actions from a high dosage of fluoxetine on neuronal and cardiac function
T2 - Drosophila, crayfish and rodent models
AU - Majeed, Zana R.
AU - Ritter, Kyle
AU - Robinson, Jonathan
AU - Blümich, Sandra L.E.
AU - Brailoiu, Eugen
AU - Cooper, Robin L.
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/8/12
Y1 - 2015/8/12
N2 - 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.
AB - 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.
KW - Heart
KW - Invertebrate
KW - Neuromuscular junction
KW - Serotonin
KW - Synapse
UR - http://www.scopus.com/inward/record.url?scp=84938907334&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84938907334&partnerID=8YFLogxK
U2 - 10.1016/j.cbpc.2015.07.010
DO - 10.1016/j.cbpc.2015.07.010
M3 - Article
C2 - 26232582
AN - SCOPUS:84938907334
SN - 1532-0456
VL - 176-177
SP - 52
EP - 61
JO - Comparative Biochemistry and Physiology Part - C: Toxicology and Pharmacology
JF - Comparative Biochemistry and Physiology Part - C: Toxicology and Pharmacology
ER -