Fluoxetine inhibits A-type potassium currents in primary cultured rat hippocampal neurons.
The effects of fluoxetine (Prozac) on the transient A-currents (IA) in primary cultured hippocampal neurons were examined using the whole-cell patch clamp technique. Fluoxetine did not significantly decrease the peak amplitude of whole-cell K+ currents, but it accelerated the decay rate of inactivation, and thus decreased the current amplitude at the end of the pulse. For further analysis, IA and delayed rectifier K+ currents (IDR) were isolated from total K+ currents. Fluoxetine decreased IA (the integral of the outward current) in a concentration-dependent manner with an IC50 of 5.54 microM. Norfluoxetine, the major active metabolite of fluoxetine, was a more potent inhibitor of IA than was fluoxetine, with an IC50 of 0.90 microM. Fluoxetine (3 microM) inhibited IA in a voltage-dependent manner over the whole range of membrane potentials tested. Analysis of the time dependence of inhibition gave estimates of 34.72 microM(-1) s(-1) and 116.39 s(-1) for the rate constants of association and dissociation, respectively. The resulting apparent Kd was 3.35 microM, similar to the IC50 value obtained from the concentration-response curve. In current clamp configuration, fluoxetine (3 microM) induced depolarization of resting membrane potential and reduced the rate of action potential. Our results indicate that fluoxetine produces a concentration- and voltage-dependent inhibition of IA, and that this effect could affect the excitability of hippocampal neurons.
Department of Physiology, Medical Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, South Korea.
Jin-Sung
JS
Choi
Bok Hee
BH
Choi
Hye Sook
HS
Ahn
Myung-Jun
MJ
Kim
Tae Hyung
TH
Han
Duck-Joo
DJ
Rhie
Shin-Hee
SH
Yoon
Yang-Hyeok
YH
Jo
Myung-Suk
MS
Kim
Sang June
SJ
Hahn
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D020128:Inhibitory Concentration 50; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D005473:Fluoxetine; D024642:Potassium Channels, Voltage-Gated; D017367:Selective Serotonin Reuptake Inhibitors