Dual Antidepressant Duloxetine Blocks Nicotinic Receptor Currents, Calcium Signals and Exocytosis in Chromaffin Cells Stimulated with Acetylcholine

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 µM. 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⁺-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 µM, 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.