Abstract

Although tricyclic antidepressant (TCA) blockade of cardiac Na⁺ channels is appreciated, actions on neuronal Na⁺ channels are less clear. Therefore, the effects of TCAs (amitriptyline, doxepin and desipramine) as well as trazadone and fluoxetine on voltage-gated Na⁺ current (I_Na) were examined in bovine adrenal chromaffin cells using the whole-cell patch-clamp method. Amitriptyline produced concentration-dependent depression of peak I_Na evoked from a holding potential of −80 mV with K_D value of 20.2 μM and a Hill coefficient of 1.2. Although 20 μM amitriptyline induced no change in the rate or voltage dependence of I_Naactivation, steady-state inactivation demonstrated a 15-mV hyperpolarizing shift. Similar results were observed for doxepin and desipramine. This shift in steady-state inactivation was associated with a slowed rate of recovery from the inactivated state. Contrasting results were observed with the atypical antidepressants: while 20 μM fluoxetine depressed peak I_Na by 61% and caused a 7-mV hyperpolarizing shift in steady-state inactivation, 100 μM trazodone decreased peak I_Na by only 19% and caused only a 3-mV shift. Although the magnitude of fluoxetine effects was similar to those of the TCAs, the onset of fluoxetine effects was substantially slower than for amitriptyline. In voltage-clamp and current-clamp measurements from neonatal rat dorsal root ganglion neurons, 20 μM amitriptyline decreased I_Na by 52% and depressed action potential dynamics consistent with enhanced Na⁺ channel inactivation. The effects of the TCAs on I_Na are similar to local anesthetic behavior and could contribute to certain analgesic actions.