Differential blockade of neuronal voltage-gated Na⁺ and K⁺ channels by antidepressant drugs

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.