Research Headquarters, Taisho Pharmaceutical Co., Ltd., Japan.
Int J Neuropsychopharmacol. 2018 Apr 1;21(4):371-381. doi: 10.1093/ijnp/pyx116.
We previously reported that serotonergic transmission plays an important role in antidepressant effects of ketamine. However, detailed mechanisms have not been elucidated. Among the serotonin receptor subtypes, the serotonin1A receptor in the medial prefrontal cortex has an important role in depression. Here, we investigated the role of the medial prefrontal cortex serotonin1A receptor and its signaling mechanism in the antidepressant effects of ketamine.
The role of serotonin1A receptor-mediated signaling mechanism (phosphoinositide-3 kinase/Akt) in the medial prefrontal cortex was examined in the mouse forced swimming test and western blotting.
Ketamine exerted antidepressant effects that lasted for 24 hours, and the sustained antidepressant effects were attenuated by intra-medial prefrontal cortex injection of a serotonin1A receptor antagonist, WAY100635. The sustained antidepressant effects were mimicked by intra- medial prefrontal cortex, but not systemic, administration of a serotonin1A receptor agonist, (±)-8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT). The sustained antidepressant effects of ketamine and 8-OH-DPAT were abrogated by intra- medial prefrontal cortex injection of a phosphoinositide-3 kinase inhibitor. Ketamine increased the phosphorylation of Akt in the medial prefrontal cortex at 60 minutes after administration, which was blocked by a serotonin1A receptor antagonist and a phosphoinositide-3 kinase inhibitor. Furthermore, the sustained antidepressant effects of ketamine and 8-OH-DPAT were attenuated by pretreatment of intra-medial prefrontal cortex injection of a mechanistic target of rapamycin complex-1 inhibitor.
These results indicate that selective stimulation of the medial prefrontal cortex serotonin1A receptor and subsequent activation of the phosphoinositide-3 kinase/Akt/mechanistic target of rapamycin complex-1 pathway may be necessary for ketamine to exert the sustained antidepressant effects, and that this mechanism could be targeted to develop a novel and effective approach for treating depression.
我们之前报道过 5-羟色胺能传递在氯胺酮的抗抑郁作用中起着重要作用。然而，其详细机制尚未阐明。在 5-羟色胺受体亚型中，内侧前额叶皮质中的 5-羟色胺 1A 受体在抑郁症中起着重要作用。在这里，我们研究了内侧前额叶皮质 5-羟色胺 1A 受体及其信号机制在氯胺酮抗抑郁作用中的作用。
在强迫游泳试验和 Western blot 中研究了内侧前额叶皮质 5-羟色胺 1A 受体介导的信号机制（磷酸肌醇-3 激酶/Akt）在其中的作用。
氯胺酮产生了持续 24 小时的抗抑郁作用，而内侧前额叶皮质注射 5-羟色胺 1A 受体拮抗剂 WAY100635 则减弱了这种持续的抗抑郁作用。内侧前额叶皮质而非全身给予 5-羟色胺 1A 受体激动剂（±）-8-羟基-2-二丙基氨基四氢萘盐酸盐（8-OH-DPAT）可模拟这种持续的抗抑郁作用。氯胺酮和 8-OH-DPAT 的持续抗抑郁作用被内侧前额叶皮质内注射磷酸肌醇-3 激酶抑制剂所阻断。氯胺酮在给药后 60 分钟增加了内侧前额叶皮质中 Akt 的磷酸化，这种作用被 5-羟色胺 1A 受体拮抗剂和磷酸肌醇-3 激酶抑制剂所阻断。此外，内侧前额叶皮质内注射雷帕霉素复合物 1 抑制剂预处理可减弱氯胺酮和 8-OH-DPAT 的持续抗抑郁作用。
这些结果表明，选择性刺激内侧前额叶皮质 5-羟色胺 1A 受体，随后激活磷酸肌醇-3 激酶/Akt/雷帕霉素复合物 1 途径，可能是氯胺酮发挥持续抗抑郁作用所必需的，并且这种机制可能成为开发新的有效治疗抑郁症方法的靶点。
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