Inhibition of neuronal Na+ channels by antidepressant drugs.
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 trazdone 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 microM and a Hill coefficient of 1.2. Although 20 microM amitriptyline induced no change in the rate or voltage dependence of INa activation, 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 microM fluoxetine depressed peak INa by 61% and caused a 7-mV hyperpolarizing shift in steady-state inactivation, 100 microM 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 microM 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.
Pancrazio
J J
JJ
Department of Anesthesiology, University of Virginia Health Sciences Center, Charlottesville, USA.
Kamatchi
G L
GL
Roscoe
A K
AK
Lynch
C
C
D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects; D051381:Rats; D026941:Sodium Channel Blockers
D000928:Antidepressive Agents; D026941:Sodium Channel Blockers; D005473:Fluoxetine; D000639:Amitriptyline