The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou University Medical College, Yangzhou, 225001, China.
Department of Pharmacy, Yangzhou University Medical College, Yangzhou, 225001, China.
Psychopharmacology (Berl). 2019 Sep;236(9):2687-2697. doi: 10.1007/s00213-019-05243-x. Epub 2019 May 3.
Antipsychotics exert therapeutic effects by modulating various cellular signalling pathways and several types of receptors, including PKA- and GSK3β-mediated signalling pathways, and NMDA receptors. The ventral midbrain, mainly containing the ventral tegmental area (VTA) and substantia nigra (SN), are the nuclei with dopamine origins in the brain, which are also involved in the actions of antipsychotics. Whether antipsychotics can modulate these cellular pathways in the ventral midbrain is unknown.
This study aims to investigate the effects of antipsychotics, including aripiprazole (a dopamine D receptor (DR) partial agonist), bifeprunox (a DR partial agonist), and haloperidol (a DR antagonist) on the PKA- and GSK3β-mediated pathways and NMDA receptors in the ventral midbrain.
Male rats were orally administered aripiprazole (0.75 mg/kg, t.i.d. (ter in die)), bifeprunox (0.8 mg/kg, t.i.d.), haloperidol (0.1 mg/kg, t.i.d.) or vehicle for either 1 week or 10 weeks. The levels of PKA, p-PKA, Akt, p-Akt, GSK3β, p-GSK3β, Dvl-3, β-catenin, and NMDA receptor subunits in the ventral midbrain were assessed by Western Blots.
The results showed that chronic antipsychotic treatment with aripiprazole selectively increased PKA activity in the VTA. Additionally, all three drugs elevated the activity of the Akt-GSK3β signalling pathway in a time-dependent manner, while only aripiprazole stimulated the Dvl-3-GSK3β-β-catenin signalling pathway in the SN. Furthermore, chronic administration with both aripiprazole and haloperidol decreased the expression of NMDA receptors.
This study suggests that activating PKA- and GSK3β-mediated pathways and downregulating NMDA receptor expression in the ventral midbrain might contribute to the clinical effects of antipsychotics.
抗精神病药通过调节各种细胞信号通路和多种类型的受体发挥治疗作用，包括 PKA 和 GSK3β 介导的信号通路和 NMDA 受体。腹侧中脑主要包含腹侧被盖区（VTA）和黑质（SN），是大脑中多巴胺起源的核团，也参与抗精神病药的作用。抗精神病药是否能调节腹侧中脑的这些细胞通路尚不清楚。
本研究旨在探讨抗精神病药，包括阿立哌唑（多巴胺 D 受体（DR）部分激动剂）、比氟平（DR 部分激动剂）和氟哌啶醇（DR 拮抗剂）对腹侧中脑 PKA 和 GSK3β 介导的通路和 NMDA 受体的影响。
雄性大鼠经口给予阿立哌唑（0.75mg/kg，tid）、比氟平（0.8mg/kg，tid）、氟哌啶醇（0.1mg/kg，tid）或载体，连续 1 周或 10 周。采用 Western Blot 法检测腹侧中脑 PKA、p-PKA、Akt、p-Akt、GSK3β、p-GSK3β、Dvl-3、β-catenin 和 NMDA 受体亚单位的水平。
结果显示，阿立哌唑慢性抗精神病治疗选择性增加了 VTA 中的 PKA 活性。此外，三种药物均呈时间依赖性增加 Akt-GSK3β 信号通路的活性，而只有阿立哌唑刺激 SN 中的 Dvl-3-GSK3β-β-catenin 信号通路。此外，阿立哌唑和氟哌啶醇的慢性给药均降低了 NMDA 受体的表达。
本研究表明，激活腹侧中脑的 PKA 和 GSK3β 介导的通路和下调 NMDA 受体表达可能是抗精神病药临床疗效的基础。
