Fluoxetine inhibits A-type potassium currents in primary cultured rat hippocampal neurons

The effects of fluoxetine (Prozac) on the transient A-currents (I _A) 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, I_A and delayed rectifier K ⁺ currents (I_DR) were isolated from total K⁺ currents. Fluoxetine decreased I_A (the integral of the outward current) in a concentration-dependent manner with an IC₅₀ of 5.54 μM. Norfluoxetine, the major active metabolite of fluoxetine, was a more potent inhibitor of I_A than was fluoxetine, with an IC₅₀ of 0.90 μM. Fluoxetine (3 μM) inhibited I_A 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 μM ^-1 s^-1 and 116.39 s^-1 for the rate constants of association and dissociation, respectively. The resulting apparent K _d was 3.35 μM, similar to the IC₅₀ value obtained from the concentration-response curve. In current clamp configuration, fluoxetine (3 μM) 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 I_A, and that this effect could affect the excitability of hippocampal neurons.