RT Journal Article
SR Electronic
T1 Dual antidepressant duloxetine blocks nicotinic receptor currents, calcium signals and exocytosis in chromaffin cells stimulated with acetylcholine
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.118.250969
DO 10.1124/jpet.118.250969
A1 CARMEN NANCLARES
A1 ISABEL GAMEIRO-ROS
A1 IAGO MENDEZ-LOPEZ
A1 CARMEN MARTINEZ-RAMIREZ
A1 JUAN F PADIN-NOGUEIRA
A1 INES COLMENA
A1 ANDRES M BARAIBAR
A1 Luis Gandia Juan
A1 Antonio Garcia Garcia
YR 2018
UL http://jpet.aspetjournals.org/content/early/2018/07/13/jpet.118.250969.abstract
AB The inhibition of nicotinic acetylcholine receptors (nAChRs) has been proposed as a potential strategy to develop new antidepressant drugs. This is based in the observation that antidepressants that selectively block noradrenaline (NA) or serotonin (5-HT) reuptake, also inhibit nAChRs. Dual antidepressants blocking both NA and 5-HT reuptake were proposed to shorten the delay in exerting their clinical effects; whether duloxetine, prototype of dual antidepressants, also block nAChRs is unknown. Here we explored this question in bovine chromaffin cells (BCCs) that express native α3, α5 and α7 nAChR and in cell lines expressing human α7, α3β4 or α4β2 nAChRs. We have found that duloxetine fully blocked the acetylcholine (ACh) elicited nicotinic currents (IACh) in BCCs with an IC50 of 0.86 µM. Such blockade seemed to be non-competitive, voltage-dependent; and partially use-dependent. Also, the ACh-elicited membrane depolarization, the elevation of cytosolic calcium ([Ca2+]c) and catecholamine release in BCCs, were also blocked by duloxetine. This blockade developed slowly and the recovery of secretion was also slow and gradual. Duloxetine did not affect Na+ or Ca2+ channel currents neither the high-K+ elicited [Ca2+]c transients and secretion. Of interest was that in cell lines expressing human α7, α3β4 and α4β2 nAChRs, duloxetine blocked nicotinic currents with IC50 of 0.1, 0.56 and 0.85 µM, respectively. Thus, in blocking α7 receptors, which are abundantly expressed in the brain, duloxetine exhibited about 10- to 100- fold higher potency with respect to reported IC50 values for various antidepressant drugs. This may contribute to the antidepressant effect of duloxetine.