TY - JOUR T1 - Inhibition of Neuronal Na<sup>+</sup> Channels by Antidepressant Drugs JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 208 LP - 214 VL - 284 IS - 1 AU - Joseph J. Pancrazio AU - Ganesan L. Kamatchi AU - Amy K. Roscoe AU - Carl Lynch III Y1 - 1998/01/01 UR - http://jpet.aspetjournals.org/content/284/1/208.abstract N2 - 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 (INa) were examined in bovine adrenal chromaffin cells using the whole-cell patch-clamp method. Amitriptyline produced concentration-dependent depression of peak INa evoked from a holding potential of −80 mV with KD 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 INaactivation, 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 INa by 61% and caused a 7-mV hyperpolarizing shift in steady-state inactivation, 100 μM trazodone decreased peak INa 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 INa by 52% and depressed action potential dynamics consistent with enhanced Na+ channel inactivation. The effects of the TCAs on INa are similar to local anesthetic behavior and could contribute to certain analgesic actions. The American Society for Pharmacology and Experimental Therapeutics ER -