Department of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan.
Int J Mol Sci. 2022 Jun 12;23(12):6571. doi: 10.3390/ijms23126571.
Several atypical antipsychotics exert mood-stabilising effects via the modulation of various monoamine receptors and intracellular signallings. Recent pharmacodynamic studies suggested that tripartite synaptic transmission can contribute to the pathophysiology of schizophrenia and mood disorders, their associated cognitive impairment, and several adverse reactions to atypical antipsychotics. Therefore, to explore the mechanisms underlying the antidepressive mood-stabilising and antipsychotic effects of brexpiprazole (Brex), we determined the effects of subchronic administration of therapeutically relevant concentrations/doses of Brex on the protein expression of 5-HT receptors, connexin43, cAMP levels, and intracellular signalling in cultured astrocytes and rat hypothalamus using ultra-high-pressure liquid chromatography with mass spectrometry and capillary immunoblotting systems. Subchronic administration of a therapeutically relevant concentration of Brex (300 nM) downregulated both 5-HT1A (5-HT1AR) and 5-HT7 (5-HT7R) receptors, in addition to phosphorylated Erk (pErk), without affecting phosphorylated Akt in the astroglial plasma membrane. Subchronic administration of 300 nM Brex decreased and increased phosphorylated AMPK and connexin43, respectively, in the astroglial cytosol fraction. A therapeutically relevant concentration of Brex acutely decreased the astroglial cAMP level, whereas, under the inhibition of 5-HT1AR, Brex did not affect astroglial cAMP levels. However, the 5-HT7R-agonist-induced increased astroglial cAMP level was inhibited by Brex. In contrast to the in vitro study, systemic subchronic administration of effective doses of Brex (3 and 10 mg/kg/day for 14 days) increased the cAMP level but did not affect phosphorylated AMPK in the rat hypothalamus. These results suggest several complicated pharmacological features of Brex. Partial 5-HT1AR agonistic action predominates in the low range of therapeutically relevant concentrations of Brex, whereas in the high range, 5-HT7R inverse agonist-like action is overlapped on the 5-HT1A agonistic action. These unique suppressive effects of Brex on 5-HT7R play important roles in the clinical features of Brex regarding its antidepressive mood-stabilising actions.
几种非典型抗精神病药通过调节各种单胺受体和细胞内信号转导发挥稳定情绪的作用。最近的药效动力学研究表明，三突触传递可以导致精神分裂症和心境障碍的病理生理学、相关认知障碍以及几种非典型抗精神病药的不良反应。因此，为了探索 Brexpiprazole（Brex）抗抑郁、稳定情绪和抗精神病作用的机制，我们使用超高效液相色谱-质谱联用和毛细管免疫印迹系统，确定了亚慢性给予治疗相关浓度/剂量的 Brex 对培养的星形胶质细胞和大鼠下丘脑 5-HT 受体、连接蛋白 43、cAMP 水平和细胞内信号的蛋白表达的影响。亚慢性给予治疗相关浓度的 Brex（300 nM）下调了 5-HT1A（5-HT1AR）和 5-HT7（5-HT7R）受体，以及磷酸化 Erk（pErk），而不影响星形胶质细胞膜质中的磷酸化 Akt。亚慢性给予 300 nM Brex 分别降低和增加了星形胶质细胞胞质部分的磷酸化 AMPK 和连接蛋白 43。治疗相关浓度的 Brex 急性降低星形胶质细胞的 cAMP 水平，而在 5-HT1AR 抑制下，Brex 不影响星形胶质细胞的 cAMP 水平。然而，Brex 抑制了 5-HT7R-激动剂诱导的星形胶质细胞 cAMP 水平的增加。与体外研究相反，全身亚慢性给予有效剂量的 Brex（3 和 10 mg/kg/天，持续 14 天）增加了 cAMP 水平，但不影响大鼠下丘脑的磷酸化 AMPK。这些结果表明 Brex 具有几种复杂的药理学特征。在治疗相关浓度的低范围内，Brex 具有部分 5-HT1AR 激动作用，而在高范围内，5-HT7R 反向激动剂样作用叠加在 5-HT1A 激动作用上。Brex 对 5-HT7R 的这种独特抑制作用在 Brex 抗抑郁、稳定情绪作用的临床特征中发挥重要作用。
