Neuropharmacology 39 (2000) 1029–1036 www.elsevier.com/locate/neuropharm Inhibition of voltage-gated calcium channels by fluoxetine in rat hippocampal pyramidal cells Ferenc Dea ´k a , Ba ´lint Laszto ´czi a , Pa ´l Pacher b , Ga ´bor L. Petheo ¨ a , Vale ´ria Kecskeme ´ti b , Andra ´s Spa ¨t a,* a Department of Physiology, Laboratory of Cellular and Molecular Physiology, Semmelweis University of Medicine, P.O. Box 259, H-1444 Budapest, Hungary b Department of Pharmacology, Semmelweis University of Medicine, P.O. Box 370, H-1445 Budapest, Hungary Accepted 12 August 1999 Abstract 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 μM. Fluoxetine decreased the high-voltage-activated (HVA) calcium current with an IC 50 between 1 and 2 μM. Nifedipine and ϖ- conotoxin GVIA inhibited the HVA current by 24% and 43%, respectively. Fluoxetine (3 μM), applied in addition to nifedipine or ϖ-conotoxin, further reduced the current. When fluoxetine (3 μM) was applied first neither nifedipine nor ϖ-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 μM 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.  2000 Elsevier Science Ltd. All rights reserved. Keywords: Depression; Epilepsy; Fluoxetine; Voltage-gated calcium channel; Hippocampus; Pyramidal neuron 1. Introduction Fluoxetine is a widely used antidepressant compound, its action is primarily attributed to inhibition of the re- uptake of serotonin in the central nervous system (Wong et al., 1995). Recent studies have indicated, however, that fluoxetine has several additional effects, including the blockade of ion channels. High concentrations (10– 100 μM) of fluoxetine have been reported to block volt- age-gated Na + (Pancrazio et al., 1998) and K + channels (Tytgat et al., 1997) in neurons and in epithelial cells, cultured from human cornea and lens (Rae et al., 1995). In smooth muscle cells, low concentrations of fluoxetine * Corresponding author. Tel.: + 36-1-266-9180; fax: + 36-1-266- 6504. E-mail address: spat@puskin.sote.hu (A. Spa ¨t). 0028-3908/00/$ - see front matter  2000 Elsevier Science Ltd. All rights reserved. PII:S0028-3908(99)00206-3 (0.1–10 μM) decreased the delayed rectifier K + current, while at higher concentrations (above 100 μM) the drug increased the calcium-activated K + current (Farrugia, 1996). Fluoxetine was found to inhibit various Cl - chan- nels (Maertens et al., 1999). Fluoxetine decreased K + -induced calcium transients in synaptosomes (Stauderman et al., 1992) suggesting that the drug inhibits voltage-gated calcium channels. This was affirmed in a rat tumor cell-line (Hahn et al., 1999), however, the channel type inhibited by the drug was not identified in these studies. The aim of the present study was to provide direct evidence for the inhibitory effect of fluoxetine on the voltage-gated calcium chan- nels in neurons, using the patch-clamp method. As some antiepileptic drugs are known to inhibit voltage-gated calcium channels, a supposed anticonvulsant action of fluoxetine (Leander, 1992) was tested in the high K + model of epilepsy.