@article {Nanclares28, author = {Carmen Nanclares and Isabel Gameiro-Ros and Iago M{\'e}ndez-L{\'o}pez and Carmen Mart{\'\i}nez-Ram{\'\i}rez and J. Fernando Pad{\'\i}n-Nogueira and In{\'e}s Colmena and Andr{\'e}s M. Baraibar and Luis Gand{\'\i}a and Antonio G. Garc{\'\i}a}, title = {Dual Antidepressant Duloxetine Blocks Nicotinic Receptor Currents, Calcium Signals and Exocytosis in Chromaffin Cells Stimulated with Acetylcholine}, volume = {367}, number = {1}, pages = {28--39}, year = {2018}, doi = {10.1124/jpet.118.250969}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The inhibition of nicotinic acetylcholine receptors (nAChRs) has been proposed as a potential strategy to develop new antidepressant drugs. This is based on 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, a prototype of dual antidepressants, also blocks nAChRs is unknown. Here we explored this question in bovine chromaffin cells (BCCs) that express native α3, α5, and α7 nAChRs and in cell lines expressing human α7, α3β4, or α4β2 nAChRs. We have found that duloxetine fully blocked the acetylcholine (ACh)-elicited nicotinic currents in BCCs with an IC50 of 0.86 {\textmu}M. Such blockade seemed to be noncompetitive, voltage dependent, and partially use dependent. 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+{\textendash}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 values of 0.1, 0.56, and 0.85 {\textmu}M, respectively. Thus, in blocking α7 receptors, which are abundantly expressed in the brain, duloxetine exhibited approximately 10-fold to 100- fold higher potency with respect to reported IC50 values for various antidepressant drugs. This may contribute to the antidepressant effect of duloxetine.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/367/1/28}, eprint = {https://jpet.aspetjournals.org/content/367/1/28.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }