Rapid and Sustained Antidepressant Action of the mGlu2/3 Receptor Antagonist MGS0039 in the Social Defeat Stress Model: Comparison with Ketamine.
Rapid and Sustained Antidepressant Action of the mGlu2/3 Receptor Antagonist MGS0039 in the Social Defeat Stress Model: Comparison with Ketamine.
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DOI：
10.1093/ijnp/pyw089
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发表时间：
2017-03-01
期刊：
影响因子：
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通讯作者：
Hashimoto K
中科院分区：
文献类型：
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作者：
Dong C;Zhang JC;Yao W;Ren Q;Ma M;Yang C;Chaki S;Hashimoto K
与N-甲基-D-天冬氨酸受体拮抗剂氯胺酮类似，代谢型谷氨酸2/3受体拮抗剂MGS0039具有抗抑郁作用。然而，在抑郁症的社会失败压力模型中，还没有将这两种化合物进行比较的报道。我们观察了MGS0039(1 mg/kg)和氯胺酮(10 mg/kg)对反复社会失败应激后易感小鼠抑郁行为的影响。检测脑源性神经营养因子TrkB、磷酸化TrkB、α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic酸受体(GluA1)、突触后密度蛋白95和树突棘密度的蛋白水平。在尾部悬吊和强迫游泳试验中，MGS0039和氯胺酮都显著减轻了易感小鼠在单次给药1或2天后观察到的不动时间的增加，与赋形剂治疗的动物相比。在蔗糖偏好测试中，这两种化合物都显著改善了单剂量药物后3至7天易感小鼠的偏好减弱。Western-Blot分析显示，与氯胺酮类似，MGS0039在单次给药8天后显著减弱了易感小鼠前额叶皮质、齿状回和海马CA3中脑源性神经营养因子、磷酸化TrkB/TrkB比率、GluA1和突触后密度蛋白95的减少。同样，与氯胺酮类似，MGS0039显著减轻了单次给药8天后易感小鼠内侧前额叶皮质、齿状回和海马CA3区的脊柱密度下降，但不能减轻内侧前额叶皮质和CA1区边缘下区域的脊椎密度下降。相反，两种药物都没有对改变的脑源性神经营养因子-TrkB信号、GluA1和突触后密度蛋白95水平产生影响，也没有增加易感小鼠伏隔核中观察到的脊椎密度。与氯胺酮类似，MGS0039在社会失败应激模型中显示出快速而持久的抗抑郁作用。这种持续的抗抑郁作用可能与内侧前额叶皮质、齿状回和CA3区的长时程突触发生有关。
Similar to the N-methyl-D-aspartate receptor antagonist ketamine, the metabotropic glutamate 2/3 receptor antagonist, MGS0039, shows antidepressant effects. However, there are no reports comparing these 2 compounds in the social defeat stress model of depression. We examined the effects of MGS0039 (1 mg/kg) and ketamine (10 mg/kg) on depression-like behavior in susceptible mice after repeated social defeat stress. Protein levels of brain-derived neurotrophic factor, TrkB, phospho-TrkB, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (GluA1), postsynaptic density protein 95, and dendritic spine density in selected brain regions were measured. In the tail suspension and forced swimming tests, both MGS0039 and ketamine significantly attenuated the increased immobility time observed in susceptible mice, compared with vehicle-treated animals, 1 or 2 days after a single dose of drug. In the sucrose preference test, both compounds significantly improved the reduced preference typically seen in susceptible mice at 3 to 7 days after a single dose of drug. Western-blot analyses showed that similar to ketamine, MGS0039 significantly attenuated the reduced brain-derived neurotrophic factor, phospho-TrkB/TrkB ratio, GluA1 and postsynaptic density protein 95 seen in the prefrontal cortex, dentate gyrus, and CA3 of the hippocampus from susceptible mice, 8 days after a single dose. Again, in a similar manner to ketamine, MGS0039 significantly attenuated the reduction of spine density in the prelimbic regions of the medial prefrontal cortex, dentate gyrus, and CA3 of the hippocampus, but not infralimbic regions of the medial prefrontal cortex and CA1, in susceptible mice 8 days after a single dose. In contrast, neither drug elicited an effect on altered brain-derived neurotrophic factor-TrkB signaling, GluA1, and postsynaptic density protein 95 levels and did not increase spine density observed in the nucleus accumbens of susceptible mice. Similar to ketamine, MGS0039 shows rapid and sustained antidepressant effects in the social defeat stress model. Long-lasting synaptogenesis in the prelimbic regions of medial prefrontal cortex, dentate gyrus, and CA3 might be implicated in this sustained antidepressant effect.