title: Mechanism of block by fluoxetine of 5-hydroxytryptamine3 (5-HT3)-mediated currents in NCB-20 neuroblastoma cells.
abstract: The effect of fluoxetine (Prozac) on 5-hydroxytryptamine(3) (5-HT(3))-mediated currents in NCB-20 neuroblastoma cells was examined using the whole-cell patch-clamp technique. Fluoxetine produced a significant reduction of peak amplitude without altering the activation time course of 5-HT(3)-mediated currents. These effects were concentration-dependent, with an IC(50) value of 4.15 microM. No voltage dependence was evident in fluoxetine's block of 5-HT(3)-mediated currents over the entire voltage range tested. The extent of block by pre-application of fluoxetine was significantly greater than that by co-application. Fluoxetine also increased the apparent rate of current desensitization to 5-HT application. Using a first-order kinetics analysis, the open-channel blocking rate constants were 0.06 microM(-1)s(-1) (k(+1), association rate constant) and 0.05 s(-1) (k(-1), dissociation rate constant), with an apparent K(d) (=k(-1)/k(+1)) of 0.83 microM. This value is close to an IC(50) of 1.11 microM obtained from the reduction in tau, the time constant of desensitization. Intracellular application of fluoxetine for long durations had no effect on the amplitude or kinetics of 5-HT(3)-mediated currents. Similarly, norfluoxetine, the major metabolite of fluoxetine, reduced the peak current, and enhanced the rate of current desensitization in a concentration-dependent manner with an IC(50) of 2.66 microM, indicating that norfluoxetine is more potent than fluoxetine in blocking 5-HT(3)-mediated currents. These results indicate that, at clinically relevant concentrations, fluoxetine and its metabolite, norfluoxetine, block 5-HT(3)-mediated currents in NCB-20 neuroblastoma cells.
authors: Department of Physiology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, South Korea.
authors: Jin-Sung
authors: JS
authors: Choi
authors: Bok Hee
authors: BH
authors: Choi
authors: Hye Sook
authors: HS
authors: Ahn
authors: Myung-Jun
authors: MJ
authors: Kim
authors: Duck-Joo
authors: DJ
authors: Rhie
authors: Shin Hee
authors: SH
authors: Yoon
authors: Do Sik
authors: DS
authors: Min
authors: Yang-Hyeok
authors: YH
authors: Jo
authors: Myung-Suk
authors: MS
authors: Kim
authors: Ki-Wug
authors: KW
authors: Sung
authors: Sang June
authors: SJ
authors: Hahn
mesh_terms: D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009447:Neuroblastoma / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D044406:Receptors, Serotonin, 5-HT3 / Q000502:physiology; D058831:Serotonin 5-HT3 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D005473:Fluoxetine; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors