Examination of methylphenidate-mediated behavior regulation by glycogen synthase kinase-3 in mice.
Examination of methylphenidate-mediated behavior regulation by glycogen synthase kinase-3 in mice.
复制标题
检查小鼠糖原合成酶激酶 3 介导的哌甲酯介导的行为调节。
DOI：
10.1016/j.ejphar.2012.10.018
复制
发表时间：
2013
影响因子：
5
通讯作者：
Jope,RichardS
中科院分区：
文献类型：
--
作者：
Mines,MarjeloA;Beurel,Eleonore;Jope,RichardS
多巴胺能活性的减弱与精神疾病有关，如注意力缺陷多动障碍（ADHD），并用治疗性兴奋剂（通常为哌甲酯或安非他明）治疗。安非他明管理增加糖原合成酶激酶-3（GSK 3）的激活，这是必要的某些急性行为反应安非他明，包括增加运动活动和受损的感觉运动门控。在这里，我们测试了通过施用GSK 3抑制剂锂或表达组成型活性GSK 3来调节GSK 3是否改变了对小鼠急性或每天施用哌甲酯8天的行为反应。将哌醋甲酯或安非他明腹膜内给予小鼠1天或8天。测量旷场活动和前脉冲抑制（PPI）。与锂对急性安非他明诱导的运动过度活跃的阻断相反，锂治疗在急性或重复给予哌甲酯8天后并没有显著降低野生型小鼠中哌甲酯诱导的运动过度活跃。锂治疗显着增加哌甲酯引起的PPI损伤，但显着减少安非他明引起的PPI赤字。在GSK 3基因敲入小鼠中，组成型活性GSK 3 β（而非GSK 3 α）的表达显著增加了急性哌甲酯治疗后的运动过度活跃，并显著损害了PPI，防止了哌甲酯诱导的PPI进一步损害，这在野生型小鼠和GSK 3 α基因敲入小鼠中是明显的。锂不抵消自发活动和PPI反应哌甲酯，因为它没有这些反应安非他明，表明不同的机制介导这些行为反应哌甲酯和安非他明。只有活性GSK 3 β而不是GSK 3 α调节对MPH的行为反应，表明GSK 3亚型的作用具有选择性。
Abnormalities in dopaminergic activity have been implicated in psychiatric diseases, such as attention deficit hyperactivity disorder (ADHD), and are treated with therapeutic stimulants, commonly methylphenidate or amphetamine. Amphetamine administration increases glycogen synthase kinase-3 (GSK3) activation, which is necessary for certain acute behavioral responses to amphetamine, including increased locomotor activity and impaired sensorimotor gating. Here, we tested if modulating GSK3 by administration of the GSK3 inhibitor lithium or expression of constitutively active GSK3 altered behavioral responses to methylphenidate administered to mice acutely or daily for 8 days. Methylphenidate or amphetamine was administered to mice intraperitoneally for 1 or 8 days. Open-field activity and pre-pulse inhibition (PPI) were measured. In contrast to lithium’s blockade of acute amphetamine-induced locomotor hyperactivity, lithium treatment did not significantly reduce methylphenidate-induced locomotor hyperactivity in wild-type mice after acute or 8 days of repeated methylphenidate administration. Lithium treatment significantly increased the impairment in PPI caused by methylphenidate, but significantly reduced the amphetamine-induced PPI deficit. In GSK3 knockin mice, expression of constitutively active GSK3β, but not GSK3α, significantly increased locomotor hyperactivity after acute methylphenidate treatment, and significantly impaired PPI, preventing further methylphenidate-induced impairment of PPI that was evident in wild-type mice and GSK3α knockin mice. Lithium does not counteract locomotor activity and PPI responses to methylphenidate as it does these responses to amphetamine, indicating that different mechanisms mediate these behavioral responses to methylphenidate and amphetamine. Only active GSK3β, not GSK3α, modulates behavioral responses to MPH, indicating selectivity in the actions of GSK3 isoforms.