Differential blockade of neuronal voltage-gated Na(+) and K(+) channels by antidepressant drugs |
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Authors: | Nicholson Graham M Blanche Tim Mansfield Kylie Tran Yvonne |
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Institution: | Department of Health Sciences, University of Technology, PO Box 123, Sydney, Broadway NSW 2007, Australia. Graham.Nicholson@uts.edu.au |
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Abstract: | The effects of a range of antidepressants were investigated on neuronal voltage-gated Na(+) and K(+) channels. With the exception of phenelzine, all antidepressants inhibited batrachotoxin-stimulated 22Na(+) uptake, most likely via negative allosteric inhibition of batrachotoxin binding to neurotoxin receptor site-2 on the Na(+) channel. Imipramine also produced a differential action on macroscopic Na(+) and K(+) channel currents in acutely dissociated rat dorsal root ganglion neurons. Imipramine produced a use-dependent block of Na(+) channels. In addition, there was a hyperpolarizing shift in the voltage-dependence of steady-state Na(+) channel inactivation and slowed repriming kinetics consistent with imipramine having a higher affinity for the inactivated state of the Na(+) channel. At higher concentrations, imipramine also blocked delayed-rectifier and transient outward K(+) currents in the absence of alterations to the voltage-dependence of activation or the kinetics of inactivation. These actions on voltage-gated ion channels may underlie the therapeutic and toxic effects of these drugs. |
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Keywords: | Na+ channel K+ channel Antidepressant Imipramine Patch clamping 22Na+ flux |
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