Kim Se Hyun, Yu Hyun-Sook, Park Hong Geun, Jeon Won Je, Song Joo Yun, Kang Ung Gu, Ahn Yong Min, Lee Young Han, Kim Yong Sik
Department of Psychiatry and Behavioral Science, Seoul National University College of Medicine, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
Prog Neuropsychopharmacol Biol Psychiatry. 2008 Oct 1;32(7):1637-42. doi: 10.1016/j.pnpbp.2008.05.027. Epub 2008 Jun 8.
Intracerebroventricular (ICV) injection of ouabain, a specific Na-K ATPase inhibitor, induced behavioral changes in rats, a putative animal model for bipolar disorder. The binding of ouabain to Na-K ATPase is known to affect signaling molecules in vitro such as extracellular signal-regulated kinase1/2 (ERK1/2). Although ERK has been suggested to be related to the behavioral alterations induced by various psychotomimetics, the effect of ouabain on ERK in the brain related to behavioral changes has not been examined. After ICV injection of ouabain in rats, we investigated changes in the phosphorylation of mitogen-activated protein kinase kinase1/2 (MEK1/2), ERK1/2, and p90 ribosomal s6 kinase (p90RSK) in rat striatum, frontal cortex, and hippocampus along with changes in locomotor activity. Ouabain induced the following biphasic dose-dependent changes in locomotor activity: no change with 10(-6) M, a statistically significant decrease with 10(-5) M, no change with 10(-4) M, and a statistically significant increase with 0.5x10(-3) and 10(-3) M. The phosphorylation level of MEK1/2, ERK1/2, and p90RSK in rat striatum showed dose-dependent changes similar to those observed in locomotor activity with relatively high correlation. The phosphorylation of these molecules in rat frontal cortex and hippocampus also changed in a similar dose-dependent pattern. Taken together, ouabain induced biphasic dose-dependent changes in locomotor activity and the phosphorylation of the ERK1/2 pathway. These findings suggest a possible relationship between ouabain-induced behavioral changes and ERK activity in the brain and suggest an important role of ERK in regulating locomotor activity and mood state.
向大鼠脑室内（ICV）注射哇巴因（一种特异性钠钾ATP酶抑制剂）会诱发大鼠行为改变，大鼠被视为双相情感障碍的一种假定动物模型。已知哇巴因与钠钾ATP酶的结合在体外会影响信号分子，如细胞外信号调节激酶1/2（ERK1/2）。尽管已有研究表明ERK与多种拟精神病药物诱发的行为改变有关，但尚未研究哇巴因对与行为变化相关的脑内ERK的影响。在向大鼠脑室内注射哇巴因后，我们研究了大鼠纹状体、额叶皮质和海马体中丝裂原活化蛋白激酶激酶1/2（MEK1/2）、ERK1/2和p90核糖体S6激酶（p90RSK）的磷酸化变化以及运动活性的变化。哇巴因在运动活性方面诱导了以下双相剂量依赖性变化：10^(-6) M时无变化，10^(-5) M时有统计学意义的降低，10^(-4) M时无变化，0.5×10^(-3) M和10^(-3) M时有统计学意义的增加。大鼠纹状体中MEK1/2、ERK1/2和p90RSK的磷酸化水平呈现出与运动活性中观察到的类似的剂量依赖性变化，且相关性相对较高。大鼠额叶皮质和海马体中这些分子的磷酸化也以类似的剂量依赖性模式发生变化。综上所述，哇巴因诱导了运动活性和ERK1/2信号通路磷酸化的双相剂量依赖性变化。这些发现表明哇巴因诱导的行为变化与脑内ERK活性之间可能存在关联，并提示ERK在调节运动活性和情绪状态中起重要作用。
