Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis 88040-900, SC, Brazil.
Pharmacol Biochem Behav. 2012 Dec;103(2):408-17. doi: 10.1016/j.pbb.2012.09.011. Epub 2012 Sep 23.
Duloxetine is a selective serotonin and noradrenaline reuptake inhibitor used as antidepressant. However, its mechanisms of action are not fully understood. This study investigated the effect of duloxetine in the mouse forced swimming test (FST) and in the tail suspension test (TST) and the involvement of the NMDA receptors and the l-arginine-NO-cGMP pathway in its effect in the FST. Duloxetine reduced the immobility time both in the FST and in the TST (dose range of 1-30mg/kg, i.p.), without changing locomotion in an open-field. Duloxetine administered orally (1-30mg/kg) also reduced the immobility time in the FST. The effect of duloxetine (10mg/kg, p.o.) in the FST was prevented by pre-treatment with NMDA (0.1pmol/site, i.c.v.), d-serine (30μg/site, i.c.v.), (l-arginine (750mg/kg, i.p.), S-nitroso-N-acetyl-penicillamine (SNAP, 25μg/site, i.c.v) or sildenafil (5mg/kg, i.p.). The administration of MK-801 (0.001mg/kg, i.p.), 7-nitroindazole (50mg/kg, i.p.), methylene blue (20mg/kg, i.p.) or 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) (30pmol/site i.c.v.) in combination with a sub-effective dose of duloxetine (0.3mg/kg, p.o.) reduced the immobility time in the FST. Moreover, the administration of duloxetine (10mg/kg) produced a reduction in NOx levels in the hippocampus and cerebral cortex. Altogether the results suggest that the effect of duloxetine in the FST is dependent on either a blockade of NMDA receptors or an inhibition of NO. In addition, our results further reinforce the role of NMDA receptors and l-arginine-NO-cGMP pathway, besides the monoaminergic systems, in the mechanism of action of current prescribed antidepressant agents.
度洛西汀是一种选择性 5-羟色胺和去甲肾上腺素再摄取抑制剂，用作抗抑郁药。然而，其作用机制尚未完全阐明。本研究探讨了度洛西汀在小鼠强迫游泳试验（FST）和悬尾试验（TST）中的作用，以及 NMDA 受体和 l-精氨酸-NO-cGMP 途径在其 FST 作用中的参与。
度洛西汀降低了 FST 和 TST 中的不动时间（剂量范围为 1-30mg/kg，ip），而对开放场中的运动没有影响。度洛西汀（1-30mg/kg，po）也降低了 FST 中的不动时间。FST 中 10mg/kg 度洛西汀的作用被 NMDA（0.1pmol/site，icv）、d-丝氨酸（30μg/site，icv）、（l-精氨酸（750mg/kg，ip）、S-亚硝基-N-乙酰青霉胺（SNAP，25μg/site，icv）或西地那非（5mg/kg，ip）预处理所预防。MK-801（0.001mg/kg，ip）、7-硝基吲唑（50mg/kg，ip）、亚甲蓝（20mg/kg，ip）或 1H-[1,2,4]恶二唑[4,3-a]喹喔啉-1-酮（ODQ）（30pmol/site，icv）与度洛西汀（0.3mg/kg，po）的亚有效剂量联合给药可降低 FST 中的不动时间。此外，度洛西汀（10mg/kg）给药可降低海马和大脑皮层中的 NOx 水平。总之，这些结果表明，FST 中度洛西汀的作用依赖于 NMDA 受体的阻断或 NO 的抑制。此外，我们的结果进一步强化了 NMDA 受体和 l-精氨酸-NO-cGMP 途径在当前处方抗抑郁药作用机制中的作用，除了单胺能系统之外。
