Inhibition of voltage-gated calcium channels by fluoxetine in rat hippocampal pyramidal cells.
Fluoxetine, an antidepressant which is used world-wide, is a prominent member of the class of selective serotonin re-uptake inhibitors. Recently, inhibition of voltage-gated Na(+) and K(+) channels by fluoxetine has also been reported. We examined the effect of fluoxetine on voltage-gated calcium channels using the patch-clamp technique in the whole-cell configuration. In hippocampal pyramidal cells, fluoxetine inhibited the low-voltage-activated (T-type) calcium current with an IC(50) of 6.8 microM. Fluoxetine decreased the high-voltage-activated (HVA) calcium current with an IC(50) between 1 and 2 microM. Nifedipine and omega-conotoxin GVIA inhibited the HVA current by 24% and 43%, respectively. Fluoxetine (3 microM), applied in addition to nifedipine or omega-conotoxin, further reduced the current. When fluoxetine (3 microM) was applied first neither nifedipine nor omega-conotoxin attenuated the remaining component of the HVA current. This observation indicates that fluoxetine inhibits both L- and N-type currents. In addition, fluoxetine inhibited the HVA calcium current in carotid body type I chemoreceptor cells and pyramidal neurons prepared from prefrontal cortex. In hippocampal pyramidal cells high K(+)-induced seizure-like activity was inhibited by 1 microM fluoxetine; the mean burst duration was shortened by an average of 44%. These results provide evidence for inhibition of T-, N- and L-type voltage-gated calcium channels by fluoxetine at therapeutically relevant concentrations.
Deák
F
F
Department of Physiology, Laboratory of Cellular and Molecular Physiology, Semmelweis University of Medicine, Budapest, Hungary.
Lasztóczi
B
B
Pacher
P
P
Petheö
G L
GL
Valéria Kecskeméti
Spät
A
A
D000200:Action Potentials; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D002344:Carotid Body / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002628:Chemoreceptor Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004622:Embryo, Mammalian; D004827:Epilepsy / Q000139:chemically induced / Q000503:physiopathology; D005473:Fluoxetine / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D015640:Ion Channel Gating; D009415:Nerve Net / Q000503:physiopathology; D011188:Potassium; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D000927:Anticonvulsants; D018687:Antidepressive Agents, Second-Generation; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D005473:Fluoxetine; D011188:Potassium; D017367:Selective Serotonin Reuptake Inhibitors