Dual antidepressant duloxetine blocks nicotinic receptor currents, calcium signals and exocytosis in chromaffin cells stimulated with acetylcholine

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 α 3 , α 5 , and α 7 nAChRs and in cell lines expressing human α 7 , α 3 β 4 , or α 4 β 2 nAChRs. We have found that duloxetine fully blocked the acetylcholine (ACh)-elicited nicotinic currents in BCCs with an IC 50 of 0.86 µ M. Such blockade seemed to be noncompetitive, voltage dependent, and partially use dependent. The ACh-elicited membrane depolarization, the elevation of cytosolic calcium ([Ca 2+ ] 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 Ca 2+ channel currents neither the high-K + –elicited [Ca 2+ ] c transients and secretion. Of interest was that in cell lines expressing human α 7 , α 3 β 4 , and α 4 β 2 nAChRs, duloxetine blocked nicotinic currents with IC 50 values of 0.1, 0.56, and 0.85 µ M, respectively. Thus, in blocking α 7 receptors, which are abundantly expressed in the brain, duloxetine exhibited approximately 10-fold to 100- fold higher potency with respect to reported IC 50 values for various antidepressant drugs. This may contribute to the antidepressant effect of duloxetine.