The Mechanism of Activity-Dependent Sodium Channel Inhibition by the Antidepressants Fluoxetine and Desipramine

Abstract

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 IC 50 values ϳ100 M at Ϫ150 mV holding potential, and ϳ1 M at Ϫ60 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 (Neuroscience

Fluoxetine Blocks Nav1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics

“…However, our IC 50 of 4.7 mM is very similar with that published by Harmer et al (2011), who reported an IC 50 of 4.9 mM using IonWorks assays from hNa v 1.5-expressing Chinese hamster ovary (CHO) cells maintained at a holding potential of 290 mV. These results suggest that the holding potential of the cell is very important to the affinity of fluoxetine for the channel, as it has been also shown in rat hippocampi neurons (Lenkey et al, 2006), suggesting that the fluoxetine binds with higher affinity to inactivated than to resting channels.…”

“…A major finding of our work was that fluoxetine shifts the steady-state inactivation curve by 6.7 mV toward more hyperpolarized values, indicating that it binds to the inactivated state of Na v 1.5, as is the case with neuronal Na 1 channels (Lenkey et al, 2006). In addition to a tonic block, fluoxetine decreased Na v 1.5 currents in a usedependent manner when pulsing at 2, 5, and 10 Hz.…”

“…Fluoxetine inhibits the serotonin transporter (SERT) in the low nanomolar range (Torres et al, 2003), but its therapeutic effect appears only at much higher plasma and brain concentrations (Muscettola et al, 1978;Bolo et al, 2000). At low micromolar concentrations, fluoxetine also targets other proteins and inhibits several types of ion channels and receptors, including the nicotinic acetylcholine receptor (Hennings et al, 1999;Eisensamer et al, 2003), voltage-gated Ca 21 channels (Deák et al, 2000;Pacher et al, 2000), volume-regulated anion channels (Maertens et al, 2002), neuronal Na 1 channels (Lenkey et al, 2006), and human ether-a-go-go-related gene, a cardiac K 1 channel (Thomas et al, 2002). The inhibition of the ether-a-go-go-related gene K 1 channel by fluoxetine occurs via two different mechanisms: 1) direct channel blockade and 2) disruption of channel protein trafficking (Rajamani et al, 2006).…”

Use-Dependent Block of Human Cardiac Sodium Channels by GS967

“…5). These differences might be attributed to a greater magnitude of effects on slow inactivation or due to differences in effects on recovery from inactivation (Lenkey et al, 2006). GS967 Effect Requires a Local Anesthetic Interaction Site.…”

Antidepressant Pharmacotherapy – Do the Benefits Outweigh the Risks?

“…While these non-specific effects have been suggested to be essential for producing the antidepressant response, the fact that we do not know the mechanism of therapeutic action of antidepressants makes it difficult to separate the beneficial from the detrimental effects of these non-specific interactions. With the reuptake blocker type of antidepressants (including TCAs and SRIs), there exists a 100-1,000 fold-magnitude of difference between the concentrations at which selective inhibition of monoamine reuptake and the therapeutic antidepressant effect occurs (Bolo et al, 2000;Torres et al, 2003;Lenkey et al, 2006). The high concentrations required for therapeutic efficacy result in a substantial loss of drug specificity.…”