Effects of fluoxetine on wild and mutant neuronal α₇ nicotinic receptors

Abstract

Fluoxetine is used in the treatment of a variety of clinical disorders including depression and obesity, and of cocaine detoxification or alcoholism. It is generally believed that fluoxetine exerts its clinical effects because it selectively blocks 5-hydroxytryptamine (5HT) reuptake into nerve terminals. In here we describe that fluoxetine antagonized the neuronal homomeric α₇ nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes, with an IC₅₀ of 43 μM, when fluoxetine was coapplied with ACh, and of 1.6 μM when the oocytes were pretreated briefly with fluoxetine. A similar block occurred in oocytes expressing L247T α₇ mutant nAChR. Furthermore, blockage of mutant α₇ receptors appeared non-competitive and was stronger with cell membrane hyperpolarization. Cell-attached single channel recordings in oocytes expressing L247T α₇ mutant nAChR showed that the voltage-dependence of the blockage by fluoxetine could be due to a drastic decrease in channel opening frequency accompanied by marked channel flickering and reduced channel conductance. We conclude that fluoxetine behaves as a reversible blocker of both wild and mutant α₇ receptors; and that the Leu-247T mutation in the channel domain renders the blockage of α₇ nAChR by fluoxetine voltage-dependent. These effects of fluoxetine on α₇ receptors may be clinically important.