1 The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou University Medical College, Yangzhou, China.
4 School of Medicine, University of Wollongong, Wollongong, NSW, Australia.
J Psychopharmacol. 2018 Nov;32(11):1252-1263. doi: 10.1177/0269881118788822. Epub 2018 Aug 23.
Antipsychotics are developed to treat mental disorders in adults; however, the prescription (mostly "off-label") of antipsychotics for children/adolescents has been constantly increasing over years. The influences of antipsychotics on juveniles requires investigation to validate their clinic use. Antipsychotics mainly exert their effects via several receptors and signaling pathways.
This study examined the effects of aripiprazole, olanzapine, and risperidone on selected signaling pathways, N-methyl-D-aspartate, and γ-aminobutyric acid A receptors in juveniles.
Rats were orally administered aripiprazole (1 mg/kg), olanzapine (1 mg/kg), risperidone (0.3 mg/kg), or vehicle three times/day from postnatal day 23 (±1 day) for three weeks. The effects of antipsychotics in the nucleus accumbens and caudate putamen were measured by Western blots.
In the nucleus accumbens, all three drugs differentially increased N-methyl-D-aspartate and γ-aminobutyric acid A receptor expression. Additionally, all three antipsychotics differentially elevated the phosphorylation of glycogen synthase kinase 3 beta, β-catenin, and cAMP-responsive element-binding protein 1. In the caudate putamen, olanzapine increased β-catenin phosphorylation; and aripiprazole and olanzapine elevated γ-aminobutyric acid A receptor levels. Correlation analysis indicated that antipsychotics might modulate N-methyl-D-aspartate receptors via glycogen synthase kinase 3 beta-β-catenin signaling and/or cAMP-responsive element-binding protein 1 activation.
These findings suggest that antipsychotics can affect protein kinase A- and glycogen synthase kinase 3 beta-dependent signaling pathways in juveniles; and their modulation on N-methyl-D-aspartate and γ-aminobutyric acid A receptors is probably through glycogen synthase kinase 3 beta-β-catenin signaling and/or cAMP-responsive element-binding protein 1 activation.
抗精神病药是为治疗成年人的精神障碍而开发的；然而，多年来，抗精神病药一直被不断地开给儿童/青少年（主要是“超适应证”）。抗精神病药对青少年的影响需要进行研究以验证其临床应用。抗精神病药主要通过几种受体和信号通路发挥作用。
本研究检测了阿立哌唑、奥氮平利培酮对青少年选定的信号通路、N-甲基-D-天冬氨酸和γ-氨基丁酸 A 受体的影响。
从出生后第 23 天（±1 天）开始，每天三次给大鼠口服阿立哌唑（1mg/kg）、奥氮平（1mg/kg）、利培酮（0.3mg/kg）或载体，连续 3 周。用 Western blot 法测定纹状体和尾状核中的药物作用。
在纹状体中，三种药物均不同程度地增加了 N-甲基-D-天冬氨酸和γ-氨基丁酸 A 受体的表达。此外，三种抗精神病药均不同程度地升高了糖原合酶激酶 3β、β-连环蛋白和 cAMP 反应元件结合蛋白 1 的磷酸化。在尾状核中，奥氮平增加了β-连环蛋白的磷酸化；阿立哌唑和奥氮平升高了γ-氨基丁酸 A 受体水平。相关性分析表明，抗精神病药可能通过糖原合酶激酶 3β-β-连环蛋白信号和/或 cAMP 反应元件结合蛋白 1 激活来调节 N-甲基-D-天冬氨酸受体。
这些发现表明，抗精神病药可影响青少年的蛋白激酶 A 和糖原合酶激酶 3β依赖性信号通路；它们对 N-甲基-D-天冬氨酸和γ-氨基丁酸 A 受体的调节可能是通过糖原合酶激酶 3β-β-连环蛋白信号和/或 cAMP 反应元件结合蛋白 1 激活。
