Fyn is required for haloperidol-induced catalepsy in mice
Fyn is required for haloperidol-induced catalepsy in mice
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DOI：
10.1074/jbc.m511608200
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发表时间：
2006-03-17
影响因子：
4.8
通讯作者：
Yuasa, S
中科院分区：
文献类型：
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作者：
Hattori, K;Uchino, S;Yuasa, S
Fyn介导的N-甲基-D-天冬氨酸（NMDA）受体亚基的酪氨酸磷酸化与多种脑功能有关，包括乙醇耐受性、学习和癫痫易感性。在这项研究中，我们探讨了Fyn在氟哌啶醇诱导的僵住症中的作用，这是一种抗精神病药物锥体外系副作用的动物模型。氟哌啶醇诱导对照小鼠的僵住症和肌肉僵硬，但这些反应在Fyn缺陷小鼠中显著降低。纹状体多巴胺D-2受体的表达，氟哌啶醇行动的主要网站，没有两种基因型之间的差异。Fyn激活和增强的NMDA受体NR 2B亚基的酪氨酸磷酸化，通过蛋白质印迹法测定，氟哌啶醇注射后诱导的对照小鼠，但这两种反应在Fyn缺陷小鼠显着减少。多巴胺D2受体阻滞剂被证明增加NR 2B磷酸化和NMDA诱导的钙反应在对照培养的纹状体神经元，但不是在Fyn缺陷的神经元。基于这些发现，我们提出了一种新的分子机制氟哌啶醇诱导的僵住症，其中多巴胺D2受体拮抗剂诱导纹状体Fyn激活和随后的酪氨酸磷酸化NR 2B改变纹状体神经元的活动，从而诱导表现为僵住反应的行为变化。
Fyn-mediated tyrosine phosphorylation of N-methyl-D-aspartate ( NMDA) receptor subunits has been implicated in various brain functions, including ethanol tolerance, learning, and seizure susceptibility. In this study, we explored the role of Fyn in haloperidol-induced catalepsy, an animal model of the extrapyramidal side effects of antipsychotics. Haloperidol induced catalepsy and muscle rigidity in the control mice, but these responses were significantly reduced in Fyn-deficient mice. Expression of the striatal dopamine D-2 receptor, the main site of haloperidol action, did not differ between the two genotypes. Fyn activation and enhanced tyrosine phosphorylation of the NMDA receptor NR2B subunit, as measured by Western blotting, were induced after haloperidol injection of the control mice, but both responses were significantly reduced in Fyn-deficient mice. Dopamine D2 receptor blockade was shown to increase both NR2B phosphorylation and the NMDA-induced calcium responses in control cultured striatal neurons but not in Fyn-deficient neurons. Based on these findings, we proposed a new molecular mechanism underlying haloperidol-induced catalepsy, in which the dopamine D2 receptor antagonist induces striatal Fyn activation and the subsequent tyrosine phosphorylation of NR2B alters striatal neuronal activity, thereby inducing the behavioral changes that are manifested as a cataleptic response.