TY - JOUR 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 DO - 10.1124/jpet.118.250969 SP - jpet.118.250969 AU - CARMEN NANCLARES AU - ISABEL GAMEIRO-ROS AU - IAGO MENDEZ-LOPEZ AU - CARMEN MARTINEZ-RAMIREZ AU - JUAN F PADIN-NOGUEIRA AU - INES COLMENA AU - ANDRES M BARAIBAR AU - Luis Gandia Juan AU - Antonio Garcia Garcia Y1 - 2018/01/01 UR - http://jpet.aspetjournals.org/content/early/2018/07/13/jpet.118.250969.abstract N2 - 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. ER -