PDF(Pubmed)
Abstract：
Sigma-1 receptor (S1R) is a unique multi-tasking chaperone protein in the endoplasmic reticulum. Since S1R agonists exhibit potent antidepressant-like activity, S1R has become a novel target for antidepression therapy. With a rapid and sustained antidepressant effect, ketamine may also interact with S1R. In this study, we investigated whether the antidepressant action of ketamine was related to S1R activation. Depression state was evaluated in the tail suspension test (TST) and a chronic corticosterone (CORT) procedure was used to induce despair-like behavior in mice. The neuronal activities and structural changes of pyramidal neurons in medial prefrontal cortex (mPFC) were assessed using fiber-optic recording and immunofluorescence staining, respectively. We showed that pharmacological manipulation of S1R modulated ketamine-induced behavioral effect. Furthermore, pretreatment with an S1R antagonist BD1047 (3 mg·kg-1·d-1, i.p., for 3 consecutive days) significantly weakened the structural and functional restoration of pyramidal neuron in mPFC caused by ketamine (10 mg·kg-1, i.p., once). Ketamine indirectly triggered the activation of S1R and subsequently increased the level of BDNF. Pretreatment with an S1R agonist SA4503 (1 mg·kg-1·d-1, i.p., for 3 consecutive days) enhanced the sustained antidepressant effect of ketamine, which was eliminated by knockdown of BDNF in mPFC. These results reveal a critical role of S1R in the sustained antidepressant effect of ketamine, and suggest that a combination of ketamine and S1R agonists may be more beneficial for depression patients.
摘要：
Sigma-1受体（S1R）是内质网中一种独特的多任务伴侣蛋白。由于S1R激动剂表现出有效的抗抑郁药样活性，S1R已成为抗抑郁治疗的新靶点。具有快速持续的抗抑郁作用，氯胺酮也可以与S1R相互作用。在这项研究中,我们调查了氯胺酮的抗抑郁作用是否与S1R激活有关.在尾悬试验（TST）中评估抑郁状态，并使用慢性皮质酮（CORT）程序在小鼠中诱导绝望样行为。内侧前额叶皮质（mPFC）锥体细胞的神经元活动和结构变化采用纤维光学记录和免疫荧光染色，分别。我们表明，S1R的药理操纵调节氯胺酮诱导的行为效应。此外，用S1R拮抗剂BD1047预处理(3mg·kg-1·d-1，腹膜内注射，连续3天）显着削弱了氯胺酮（10mg·kg-1，i.p.once).氯胺酮间接触发S1R的激活，随后增加BDNF的水平。用S1R激动剂SA4503（1mg·kg-1·d-1，腹膜内，连续3天）增强了氯胺酮的持续抗抑郁作用，mPFC中BDNF的敲低消除。这些结果揭示了S1R在氯胺酮的持续抗抑郁作用中的关键作用，并提示氯胺酮和S1R激动剂联合使用可能对抑郁症患者更有益。
