EFFECTS OF FLUOXETINE ON WILD AND MUTANT NEURONAL ALPHA(7) NICOTINIC RECEPTORS

Fluoxetine is used in the treatment of a variety of clinical disorders including depression and obesity, and of cocaine detoxification or al coholism. It is generally believed that fluoxetine exerts its clinical effects because it selectively blocks 5-hydroxytryptamine (5HT) reupt ake into nerve terminals. In here we describe that fluoxetine antagoni zed the neuronal homomeric alpha(7) nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes, with an IC50 of 43 mu M, when fl uoxetine was coapplied with ACh, and of 1.6 mu M when the oocytes were pretreated briefly with fluoxetine. A similar block occurred in oocyt es expressing L247T alpha(7) mutant nAChR. Furthermore, blockage of mu tant alpha(7) receptors appeared non-competitive and was stronger with cell membrane hyperpolarization. Cell-attached single channel recordi ngs in oocytes expressing L247T alpha(7) mutant nAChR showed that the voltage-dependence of the blockage by fluoxetine could be due to a dra stic decrease in channel opening frequency accompanied by marked chann el flickering and reduced channel conductance. We conclude that fluoxe tine behaves as a reversible blocker of both wild and mutant alpha(7) receptors; and that the Leu-247T mutation in the channel domain render s the blockage of alpha(7) nAChR by fluoxetine voltage-dependent. Thes e effects of fluoxetine on alpha(7) receptors may be clinically import ant.