Department of Psychiatry and Behavioral Science & Institute of Human Behavioral Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Prog Neuropsychopharmacol Biol Psychiatry. 2013 Aug 1;45:73-82. doi: 10.1016/j.pnpbp.2013.04.018. Epub 2013 May 2.
Intracerebroventricular (ICV) injection of ouabain, a specific Na/K-ATPase inhibitor, induces behavioral changes in rats in a putative animal model of mania. The binding of ouabain to Na/K-ATPase affects signaling molecules in vitro, including ERK1/2 and Akt, which promote protein translation. We have also reported that ERK1/2 and Akt in the brain are involved in the ouabain-induced hyperactivity of rats. In this study, rats were given an ICV injection of ouabain, and then their frontal cortices were examined to determine the effects of ouabain on the mTOR/p70S6K/S6 signaling pathway and protein translation, which are important in modifications of neural circuits and behavior. Rats showed ouabain-induced hyperactivity up to 8h following injection, and increased phosphorylation levels of mTOR, p70S6K, S6, eIF4B, and 4E-BP at 1, 2, 4, and 8h following ouabain injection. Immunohistochemical analyses revealed that increased p-S6 immunoreactivity in the cytoplasm of neurons by ouabain was evident in the prefrontal, cingulate, and orbital cortex. These findings suggested increased translation initiation in response to ouabain. The rate of protein synthesis was measured as the amount of [(3)H]-leucine incorporation in the cell-free extracts of frontal cortical tissues, and showed a significant increase at 8h after ouabain injection. These results suggest that ICV injection of ouabain induced activation of the protein translation initiation pathway regulated by ERK1/2 and Akt, and prolonged hyperactivity in rats. In conclusion, protein translation pathway could play an important role in ouabain-induced hyperactivity in a rodent model of mania.
脑室（ICV）注射哇巴因，一种特定的 Na/K-ATP 酶抑制剂，可在大鼠中诱导行为变化，这是一种可能的躁狂症动物模型。哇巴因与 Na/K-ATP 酶的结合会影响体外的信号分子，包括 ERK1/2 和 Akt，它们促进蛋白质翻译。我们还报告说，大脑中的 ERK1/2 和 Akt 参与了哇巴因诱导的大鼠过度活跃。在这项研究中，大鼠接受脑室注射哇巴因，然后检查其前额皮质，以确定哇巴因对 mTOR/p70S6K/S6 信号通路和蛋白质翻译的影响，这在神经回路和行为的修饰中很重要。大鼠在注射后 8 小时内表现出哇巴因诱导的过度活跃，并且在注射哇巴因后 1、2、4 和 8 小时，mTOR、p70S6K、S6、eIF4B 和 4E-BP 的磷酸化水平增加。免疫组织化学分析显示，哇巴因引起的神经元细胞质中 p-S6 免疫反应性增加在前额皮质、扣带皮质和眶额皮质中明显。这些发现表明，蛋白质翻译起始对哇巴因的反应增加。蛋白质合成率作为前额皮质组织无细胞提取物中 [(3)H]-亮氨酸掺入的量来测量，并且在哇巴因注射后 8 小时显示出显著增加。这些结果表明，脑室注射哇巴因诱导 ERK1/2 和 Akt 调节的蛋白质翻译起始途径的激活，并延长大鼠的过度活跃。总之，蛋白质翻译途径可能在躁狂症啮齿动物模型中哇巴因诱导的过度活跃中起重要作用。
