Long-lasting antidepressant action of ketamine, but not glycogen synthase kinase-3 inhibitor SB216763, in the chronic mild stress model of mice.
Long-lasting antidepressant action of ketamine, but not glycogen synthase kinase-3 inhibitor SB216763, in the chronic mild stress model of mice.
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在小鼠慢性轻度应激模型中，氯胺酮而非糖原合酶激酶 3 抑制剂 SB216763 具有持久抗抑郁作用
DOI：
10.1371/journal.pone.0056053
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hashimoto K
中科院分区：
文献类型：
--
作者：
Ma XC;Dang YH;Jia M;Ma R;Wang F;Wu J;Gao CG;Hashimoto K
临床研究表明，n -甲基- d -天冬氨酸（NMDA）受体拮抗剂氯胺酮对屈光性重度抑郁症和双相抑郁症患者具有快速的抗抑郁作用。这种快速起效使氯胺酮成为对患者非常有吸引力的药物，特别是对那些通常对治疗没有反应的患者。最近的一项研究表明，糖原合成酶激酶(GSK)-3可能是氯胺酮快速抗抑郁作用的基础，尽管确切的机制尚不清楚。在这项研究中，我们研究了氯胺酮和GSK-3抑制剂SB216763在不可预测的慢性轻度应激（CMS）小鼠模型中的作用。方法/主要发现将成年C57/B6雄性小鼠分为非应激对照组和不可预测的CMS （35 d）组。然后，将氯胺酮（10 mg/kg）或建立的GSK-3抑制剂SB216763 （10 mg/kg）分别给予CMS组小鼠，对照组给予对照剂。在野外试验中，4组（对照+载药、CMS+载药、CMS+氯胺酮、CMS+SB216763）间无差异。在蔗糖摄入试验中，在CMS小鼠中观察到的1%的蔗糖摄入量下降在单剂量氯胺酮后显著减弱，而SB216763则没有。在悬尾试验（TST）和强迫游泳试验（FST）中，单剂量氯胺酮显著减弱CMS小鼠的静止时间，而SB216763则没有。有趣的是，单次服用氯胺酮后，氯胺酮诱导的蔗糖摄入量增加持续了8天。此外，单次给药氯胺酮，而不是SB216763，显著缩短了对照组（非应激）小鼠的TST和FST的静止时间。这些发现表明，单次给药氯胺酮，而不是GSK-3抑制剂SB216763，在CMS模型小鼠中产生持久的抗抑郁作用。
Background Clinical studies demonstrate that the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, induces rapid antidepressant effects in patients with refractive major depressive disorder and bipolar depression. This rapid onset of action makes ketamine a highly attractive drug for patients, particularly those who do not typically respond to therapy. A recent study suggested that glycogen synthase kinase (GSK)-3 may underlie the rapid antidepressant action of ketamine, although the precise mechanisms are unclear. In this study, we examined the effects of ketamine and GSK-3 inhibitor SB216763 in the unpredictable, chronic mild stress (CMS) mouse model of mice. Methodology/Principal Findings Adult C57/B6 male mice were divided into 2 groups, a non-stressed control group and the unpredictable CMS (35 days) group. Then, either vehicle, ketamine (10 mg/kg), or the established GSK-3 inhibitor, SB216763 (10 mg/kg), were administered into mice in the CMS group, while vehicle was administered to controls. In the open field test, there was no difference between the four groups (control+vehicle, CMS+vehicle, CMS+ketamine, CMS+SB216763). In the sucrose intake test, a 1% sucrose intake drop, seen in CMS mice, was significantly attenuated after a single dose of ketamine, but not SB216763. In the tail suspension test (TST) and forced swimming test (FST), the increased immobility time seen in CMS mice was significantly attenuated by a single dose of ketamine, but not SB216763. Interestingly, the ketamine-induced increase in the sucrose intake test persisted for 8 days after a single dose of ketamine. Furthermore, a single administration of ketamine, but not SB216763, significantly attenuated the immobility time of the TST and FST in the control (non-stressed) mice. Conclusions/Significance These findings suggest that a single administration of ketamine, but not GSK-3 inhibitor SB216763, produces a long-lasting antidepressant action in CMS model mice.
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DOI：
10.1126/science.1190287
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li N;Lee B;Liu RJ;Banasr M;Dwyer JM;Iwata M;Li XY;Aghajanian G;Duman RS
通讯作者：
Duman RS
DOI：
10.1017/s1461145704004535
发表时间：
2004-12-01
影响因子：
4.8
作者：
Gould, TD;Einat, H;Manji, HK
通讯作者：
Manji, HK
DOI：
10.1017/s1461145708009516
发表时间：
2009-04-01
影响因子：
4.8
作者：
Block, Wolfgang;Traeber, Frank;Jessen, Frank
通讯作者：
Jessen, Frank
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH
影响因子：
10.6
作者：
Auer, DP;Pütz, B;Holsboer, F
通讯作者：
Holsboer, F