Collo Ginetta, Cavalleri Laura, Merlo Pich Emilio
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Neuroscience Therapeutic Area Unit, Takeda Pharmaceuticals International, Zurich, Switzerland.
Chronic Stress (Thousand Oaks). 2019 Apr 10;3:2470547019842545. doi: 10.1177/2470547019842545. eCollection 2019 Jan-Dec.
The mechanisms underlying the antidepressant effects of ketamine in treatment-resistant depression are only partially understood. Reactivation of neural plasticity in prefrontal cortex has been considered critical in mediating the effects of standard antidepressants, but in treatment-resistant depression patients with severe anhedonia, other components of the affected brain circuits, for example, the dopamine system, could be involved. In a recent article in , we showed that ketamine induces neural plasticity in human and mouse dopaminergic neurons. Human dopaminergic neurons were differentiated from inducible pluripotent stem cells for over 60 days. Mimicking the pharmacokinetic exposures occurring in treatment-resistant depression subjects, cultures were incubated with either ketamine at 0.1 and 1 µM for 1 h or with its active metabolite (2R,6R)-hydroxynorketamine at 0.1 and 0.5 µM for up to 6 h. Three days after dosing, we observed a concentration-dependent increase in dendritic arborization and soma size. These effects were mediated by the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor that triggered the pathways of mammalian target of rapamycin and extracellular signal-regulated kinase via the engagement of brain-derived neurotrophic factor signaling, as previously described in rodent prefrontal cortex. Interestingly, we found that neural plasticity induced by ketamine requires functionally intact dopamine D3 receptors. These data are in keeping with our recent observation that plasticity can be induced in human dopaminergic neurons by the D3 receptor-preferential agonist pramipexole, whose effect as augmentation treatment in treatment-resistant depression has been reported. Overall, the evidence of pharmacologic response in human inducible pluripotent stem cell-derived neurons could provide complementary information to those provided by circuit-based imaging when assessing the potential response to a given augmentation treatment.
氯胺酮治疗难治性抑郁症的抗抑郁作用机制仅得到部分理解。前额叶皮质神经可塑性的重新激活被认为在介导标准抗抑郁药的作用中起关键作用，但在伴有严重快感缺失的难治性抑郁症患者中，受影响脑回路的其他成分，例如多巴胺系统，可能也参与其中。在最近发表于某期刊的一篇文章中，我们表明氯胺酮可诱导人和小鼠多巴胺能神经元的神经可塑性。人多巴胺能神经元由诱导多能干细胞分化超过60天。模拟难治性抑郁症患者体内发生的药代动力学暴露情况，将培养物分别用0.1和1 μM氯胺酮孵育1小时，或用0.1和0.5 μM其活性代谢物(2R,6R)-羟基去甲氯胺酮孵育长达6小时。给药三天后，我们观察到树突分支和胞体大小呈浓度依赖性增加。如先前在啮齿动物前额叶皮质中所描述的，这些效应是由α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体的激活介导的，该受体通过脑源性神经营养因子信号通路的参与触发雷帕霉素哺乳动物靶标和细胞外信号调节激酶的信号通路。有趣的是，我们发现氯胺酮诱导的神经可塑性需要功能完整的多巴胺D3受体。这些数据与我们最近的观察结果一致，即D3受体选择性激动剂普拉克索可诱导人多巴胺能神经元的可塑性，并且已有报道其作为难治性抑郁症增效治疗的效果。总体而言，在评估对给定增效治疗的潜在反应时，人诱导多能干细胞衍生神经元中药物反应的证据可为基于脑回路成像提供的信息提供补充。
