Inhibition of neuronal K-v potassium currents by the antidepressant drug, fluoxetine

1 The effect of the antidepressant drug, fluoxetine on neuronal delayed rec tifier (K-v) potassium (K) currents was investigated using perforated-patch whole-cell electrophysiological recording methods. 2 Fluoxetine was an effective inhibitor of K-v currents in cerebellar granu le neurons (CGNs) and also inhibited recombinant K(v)1.1 channels expressed in Chinese hamster ovary (CHO) cells. 3 Fluoxetine had an IC50 of 11 mu M in CGNs but was slightly less potent on K(v)1.1 channels (IC50 = 55 mu M) Interestingly, fluoxetine was a much mor e potent inhibitor of K(v)1.1 expressed in mammalian cells than has been fo und previously for the same homomeric channel expressed in Xenopus oocytes. 4 At concentrations that produced around 50% block, the shape of the K-v cu rrents in the presence of fluoxetine was simply scaled down when compared t o control currents. 5 The effect of fluoxetine on K-v currents in CGNs was neither voltage-depe ndent nor dependent on the channels being in their open state. Both of thes e observations suggest that fluoxetine does not act as a simple open channe l blocking agent. 6 It is concluded that block of K-v currents in mammalian neurons can occur at therapeutic levels of fluoxetine. This could lead to an increase in neu ronal excitability and this effect may contribute to the therapeutic antide pressant action of fluoxetine.