%0 Journal Article %A N. Lenkey %A R. Karoly %A J. P. Kiss %A B. K. Szasz %A E. S. Vizi %A A. Mike %T The Mechanism of Activity-Dependent Sodium Channel Inhibition by the Antidepressants Fluoxetine and Desipramine %D 2006 %R 10.1124/mol.106.026419 %J Molecular Pharmacology %P 2052-2063 %V 70 %N 6 %X The effect of monoamine uptake inhibitor-type antidepressants on sodium channels of hippocampal neurons was investigated. Members of the tricyclic group of antidepressants are known to modify multiple targets, including sodium channels, whereas selective serotonin-reuptake inhibitors (SSRIs) are regarded as highly selective compounds, and their effect on sodium channels was not investigated in detail. In this study, a representative member of each group was chosen: the tricyclic antidepressant desipramine and the SSRI fluoxetine. The drugs were roughly equipotent use-dependent inhibitors of sodium channels, with IC50 values ∼100 μMat -150 mV holding potential, and ∼1 μMat -60 mV. We suggest that therapeutic concentrations of antidepressants affect neuronal information processing partly by direct, activity-dependent inhibition of sodium channels. As for the mechanism of inhibition, use-dependent inhibition by antidepressants was believed to be due to a preferential affinity to the fast-inactivated state. Using a voltage and perfusion protocol by which relative affinities to fast-versus slow-inactivated states could be assessed, we challenged this view and found that the affinity of both drugs to slowinactivated state(s) was higher. We propose a different mechanism of action for these antidepressants, in which slow rather than fast inactivation plays the dominant role. This mechanism is similar but not equivalent with the novel mechanism of usedependent sodium channel inhibition previously described by our group (Neuroscience125:1019-1028, 2004; Neuroreport14:1945-1949, 2003). Our results suggest that different drugs can produce use-dependent sodium channel inhibition by different mechanisms. The American Society for Pharmacology and Experimental Therapeutics %U https://molpharm.aspetjournals.org/content/molpharm/70/6/2052.full.pdf