Effects of the antipsychotics haloperidol, clozapine, and aripiprazole on the dendritic spine
Effects of the antipsychotics haloperidol, clozapine, and aripiprazole on the dendritic spine
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DOI：
10.1016/j.euroneuro.2018.03.004
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发表时间：
2018-05
影响因子：
5.6
通讯作者：
M. Takaki;M. Kodama;Y. Mizuki;Hiroki Kawai;Bunta Yoshimura;M. Kishimoto;S. Sakamoto;Y. Okahisa;N. Yamada
中科院分区：
文献类型：
--
作者：
M. Takaki;M. Kodama;Y. Mizuki;Hiroki Kawai;Bunta Yoshimura;M. Kishimoto;S. Sakamoto;Y. Okahisa;N. Yamada
三种类型的抗精神病药，典型的（如氟哌啶醇），非典型的（如氯氮平），和多巴胺部分激动剂（如阿立哌唑），用于治疗精神分裂症。这些抗精神病药物具有不同的疗效和副作用。我们研究了阿立哌唑、氯氮平和氟哌啶醇是否通过AKT-GSK-3 β级联差异调节树突棘。制备来自Sprague-Dawley大鼠的分离的皮层神经元并培养28天。阿立哌唑、氯氮平或氟哌啶醇给予大鼠皮层神经元。Western blot检测PSD 95蛋白和AKT-GSK-3 β级联相关蛋白水平。用免疫荧光细胞染色法观察棘的数目和PSD 95斑点的数目。阿立哌唑（1 µM或10 µM）和氯氮平（1 µM）增加了PSD 95蛋白的水平、棘的数量、磷酸化Akt Thr 308和Ser 473以及磷酸化GSK-3 β Ser 9。另一方面，氟哌啶醇（1 µM或10 µM）或不适当浓度的氯氮平（10 µM）会降低它们。GSK抑制剂也增加PSD-95蛋白的水平，并导致相同的形态。阿立哌唑、氯氮平和氟哌啶醇对树突棘的调节不同，这种作用可能通过AKT-GSK-3 β级联反应发生。抗精神病药物的选择和剂量对精神分裂症患者树突棘的保护可能很重要。
Three types of antipsychotics, typical (e.g. haloperidol), atypical (e.g. clozapine), and dopamine partial agonist (e.g. aripiprazole), are administered for treatment of schizophrenia. These antipsychotics have different efficacy and side-effect profiles. We investigated whether aripiprazole, clozapine, and haloperidol differentially regulate the dendritic spine through the AKT-GSK-3 beta cascade. Dissociated cortical neurons from Sprague-Dawley rats were prepared and cultured for 28 days. Aripiprazole, clozapine, or haloperidol was administered to the rat cortical neurons. The levels of PSD95 protein and AKT-GSK-3 beta cascade-related proteins were investigated by Western blot. The number of spines and PSD95 puncta were investigated by immunofluorescence cell staining. Aripiprazole (1 µM or 10 µM) and clozapine (1 µM) increased the levels of PSD95 protein, the number of spines, phosphorylated Akt Thr308 and Ser473, and phosphorylated GSK-3 beta Ser9. On the other hand, haloperidol (1 µM or 10 µM) or an inappropriate concentration of clozapine (10 µM) decreased them. A GSK inhibitor also increased the levels of PSD-95 protein and caused the same morphology. Aripiprazole, clozapine, and haloperidol differentially regulate the dendritic spine, and this effect may occur through the AKT-GSK-3 beta cascade. Selection and appropriate dose of these antipsychotics may be important for the protection of dendritic spines in patients with schizophrenia.