Involvement of nitric oxide (NO) signaling pathway in the antidepressant action of bupropion, a dopamine reuptake inhibitor
Involvement of nitric oxide (NO) signaling pathway in the antidepressant action of bupropion, a dopamine reuptake inhibitor
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DOI：
10.1016/j.ejphar.2007.04.028
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发表时间：
2007-07-30
影响因子：
5
通讯作者：
Kulkarni, S. K.
中科院分区：
文献类型：
--
作者：
Dhir, Ashish;Kulkarni, S. K.
本研究旨在阐明多巴胺再摄取抑制剂安非他酮[（+/-）-α-叔丁基氨基-3-氯苯丙酮]抗抑郁作用的各种行为学和神经化学基础的改变及其可能的作用机制。研究了L-精氨酸-一氧化氮（NO）-环磷酸鸟苷（cGMP）信号通路在安非他酮抗抑郁作用中的作用，以及安非他酮对去甲肾上腺素、多巴胺和高香草酸等脑递质的作用。安非他酮（10、15、20和40 mg/kg.，注射用）对小鼠强迫游泳和悬尾不动期的影响呈剂量依赖性。发现安非他酮在减少不动期方面的ED 50值为18.5和18 mg/kg i. p.，分别进行强迫游泳试验和悬尾试验。安非他酮（10、20和40 mg/kg.，注射用）也逆转了利血平诱导的行为绝望。当不同剂量（10、15、20和40 mg/kg.，注射用）安非他酮的自发活动进行了测试，它（15，20和40 mg/kg，注射用）增加自发活动。在20和40 mg/kg剂量下，药物显示体温过低。脑样品的神经化学分析显示安非他酮剂量依赖性地（10-40 mg/kg，注射用）增加小鼠全脑多巴胺和高香草酸的含量。在20 mg/kg剂量下，去甲肾上腺素水平也升高。安非他酮（20 mg/kg.，注射用）用L-精氨酸（750 mg/kg，注射用）[一氧化氮合酶（NOS）的底物]。用7-硝基吲唑（25 mg/kg.，注射用）[一种特异性神经元型一氧化氮合酶（nNOS）抑制剂]对亚有效剂量的安非他酮（10 mg/kg，i. p.）的作用产生增强作用。此外，用亚甲蓝（10 mg/kg.，注射用）[一氧化氮合酶（NOS）和可溶性鸟苷酸环化酶（sGC）的直接抑制剂]增强安非他酮（10 mg/kg.，注射用）在强迫游泳测试中。此外，安非他酮（20 mg/kg.，注射用）也被西地那非（5 mg/kg.，注射用）[磷酸二酯酶5抑制剂]。研究表明，安非他酮通过其多巴胺能和/或通过调节L-精氨酸-一氧化氮（NO）-环磷酸鸟苷（cGMP）信号通路在不同的抑郁症动物模型中具有抗抑郁活性。(C)2007 Elsevier B. V.保留所有权利。
The present study was undertaken to elucidate the alterations in various behavioral and neurochemical basis of antidepressant action of bupropion [(+/-)-alpha-t-butylamino-3-chloropropiophenone], a dopamine reuptake inhibitor and to elucidate the possible mechanism of its action. The involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of bupropion was investigated besides its actions on various brain transmitters like norepinephrine, dopamine and homovanillic acid. Bupropion (10, 15, 20 and 40 mg/kg., i.p.) dose dependently inhibited the immobility period in mice in both forced swim test and tail suspension test. ED50 values of bupropion in reducing the immobility period was found to be 18.5 and 18 mg/kg i.p., in forced swim test and tail suspension test, respectively. Bupropion (10, 20 and 40 mg/kg., i.p.) reversed the reserpine-induced behavioral despair also. When different doses (10, 15, 20 and 40 mg/kg., i.p.) of bupropion were tested for locomotor activity, it (15, 20 and 40 mg/kg., i.p.) increased locomotor activity. At 20 and 40 mg/kg doses the drug showed hypothermia. The neurochemical analysis of brain samples revealed that bupropion dose dependently (10-40 mg/kg., i.p.) increased the brain contents of dopamine and homovanillic acid in the mouse whole brain. The levels of norepinephrine were also increased at 20 mg/kg dose. The antidepressant-like effect of bupropion (20 mg/kg., i.p.) was prevented by pretreatment with L-arginine (750 mg/kg., i.p.) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (25 mg/kg., i.p.) [a specific neuronal nitric oxide synthase (nNOS) inhibitor] produced potentiation of the action of subeffective dose of bupropion (10 mg/kg i.p.). In addition, treatment of mice with methylene blue (10 mg/kg., i.p.) [direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] potentiated the effect of bupropion (10 mg/kg., i.p.) in the forced swim test. Furthermore, the reduction in the immobility period elicited by bupropion (20 mg/kg., i.p.) was also inhibited by pretreatment with sildenafil (5 mg/kg., i.p.) [phosphodiesterase 5 inhibitor]. The study indicated that bupropion possesses antidepressant activities in different animal models of depression through its dopaminergic and/or by modulating the L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway. (C) 2007 Elsevier B.V. All rights reserved.