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

Abstract

1. The effect of the antidepressant drug, fluoxetine on neuronal delayed rectifier (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 granule 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 μM in CGNs but was slightly less potent on K(v)1.1 channels (IC50 = 55 μM). Interestingly, fluoxetine was a much more potent inhibitor of K(v)1.1 expressed in mammalian cells than has been found previously for the same homomeric channel expressed in Xenopus oocytes. 4. At concentrations that produced around 50% block, the shape of the K(v) currents in the presence of fluoxetine was simply scaled down when compared to control currents. 5. The effect of fluoxetine on K(v) currents in CGNs was neither voltage-dependent nor dependent on the channels being in their open state. Both of these observations suggest that fluoxetine does not act as a simple open channel 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 neuronal excitability and this effect may contribute to the therapeutic antidepressant action of fluoxetine.