Instituto Teófilo Hernando and Departamento de Farmacología, Facultad de Medicina (C.N., I.G.-R., I.M.-L., C.M.-R., J.F.P.-N., I.C., A.M.B., L.G., A.G.G.) and Instituto de Investigación Sanitaria, Hospital Universitario de La Princesa (A.G.G.), Universidad Autónoma de Madrid, Madrid, Spain; and Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla La Mancha (UCLM), Ciudad Real, Spain (J.F.P.-N.).
Instituto Teófilo Hernando and Departamento de Farmacología, Facultad de Medicina (C.N., I.G.-R., I.M.-L., C.M.-R., J.F.P.-N., I.C., A.M.B., L.G., A.G.G.) and Instituto de Investigación Sanitaria, Hospital Universitario de La Princesa (A.G.G.), Universidad Autónoma de Madrid, Madrid, Spain; and Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla La Mancha (UCLM), Ciudad Real, Spain (J.F.P.-N.)
J Pharmacol Exp Ther. 2018 Oct;367(1):28-39. doi: 10.1124/jpet.118.250969. Epub 2018 Jul 13.
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 , , and nAChRs and in cell lines expressing human , , or nAChRs. We have found that duloxetine fully blocked the acetylcholine (ACh)-elicited nicotinic currents in BCCs with an IC of 0.86 M. Such blockade seemed to be noncompetitive, voltage dependent, and partially use dependent. The ACh-elicited membrane depolarization, the elevation of cytosolic calcium ([Ca]), 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 channel currents neither the high-K-elicited [Ca] transients and secretion. Of interest was that in cell lines expressing human , , and nAChRs, duloxetine blocked nicotinic currents with IC values of 0.1, 0.56, and 0.85 M, respectively. Thus, in blocking receptors, which are abundantly expressed in the brain, duloxetine exhibited approximately 10-fold to 100- fold higher potency with respect to reported IC values for various antidepressant drugs. This may contribute to the antidepressant effect of duloxetine.
烟碱型乙酰胆碱受体 (nAChRs) 的抑制被认为是开发新型抗抑郁药物的潜在策略。这是基于这样的观察结果，即选择性阻断去甲肾上腺素 (NA) 或 5-羟色胺 (5-HT) 再摄取的抗抑郁药也抑制 nAChRs。同时阻断 NA 和 5-HT 再摄取的双重抗抑郁药被提议缩短发挥其临床效果的延迟；是否双通道抗抑郁药度洛西汀也阻断 nAChRs 尚不清楚。在这里，我们在表达天然 、 、 和 nAChRs 的牛肾上腺嗜铬细胞 (BCC) 和表达人 、 或 nAChRs 的细胞系中探讨了这个问题。我们发现度洛西汀完全阻断了 BCC 中乙酰胆碱 (ACh) 引发的烟碱电流，IC 为 0.86 M。这种阻断似乎是非竞争性的、电压依赖性的和部分使用依赖性的。ACh 引发的膜去极化、细胞内钙 ([Ca]) 的升高和 BCC 中儿茶酚胺的释放也被度洛西汀阻断。这种阻断发展缓慢，分泌的恢复也缓慢而逐渐。度洛西汀不影响 Na 或 Ca 通道电流，也不影响高 K 引发的 [Ca] 瞬变和分泌。有趣的是，在表达人 、 、 和 nAChRs 的细胞系中，度洛西汀分别以 0.1、0.56 和 0.85 M 的 IC 值阻断烟碱电流。因此，在阻断大量表达于大脑中的 受体方面，度洛西汀对各种抗抑郁药的报道 IC 值表现出约 10 倍至 100 倍的更高效力。这可能有助于度洛西汀的抗抑郁作用。
