PT - JOURNAL ARTICLE AU - Pancrazio, Joseph J. AU - Kamatchi, Ganesan L. AU - Roscoe, Amy K. AU - Lynch, Carl TI - Inhibition of Neuronal Na<sup>+</sup> Channels by Antidepressant Drugs DP - 1998 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 208--214 VI - 284 IP - 1 4099 - http://jpet.aspetjournals.org/content/284/1/208.short 4100 - http://jpet.aspetjournals.org/content/284/1/208.full SO - J Pharmacol Exp Ther1998 Jan 01; 284 AB - 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