Reversal of supersensitive striatal dopamine D1 receptor signaling and extracellular signal-regulated kinase activity in dopamine-deficient mice
Reversal of supersensitive striatal dopamine D1 receptor signaling and extracellular signal-regulated kinase activity in dopamine-deficient mice
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DOI：
10.1016/j.neuroscience.2005.10.054
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发表时间：
2006-01-01
期刊：
影响因子：
3.3
通讯作者：
Gerfen, CR
中科院分区：
文献类型：
--
作者：
Kim, DS;Palmiter, RD;Gerfen, CR
黑质纹状体多巴胺能神经元的损伤引起纹状体对多巴胺的超敏感性。以前的工作已经表明，这种超敏感性，一个重要方面的啮齿动物模型的帕金森氏病，是与解剖学异常模式激活的细胞外信号调节激酶。多巴胺能神经元损伤后，多巴胺D-1受体激动剂激活细胞外信号调节激酶在背侧纹状体，在完整的动物中没有观察到的东西。在这里，我们使用了一种更具选择性的多巴胺耗竭方法。多巴胺缺陷小鼠，其中酪氨酸羟化酶基因是专门失活的多巴胺能神经元，被用来研究多巴胺D-1受体介导的细胞外信号调节激酶的激活。在野生型小鼠中，用多巴胺D1-受体激动剂急性治疗导致在背侧纹状体中没有激活的背侧纹状体中的髓核中的细胞外信号调节激酶的激活。相反，在多巴胺缺乏的小鼠中，多巴胺D-1受体激动剂治疗导致细胞外信号调节激酶的激活，不仅在延髓核，而且在整个背侧纹状体的大部分。通过反复注射左旋多巴36小时来慢性替代多巴胺可逆转这种超敏感的细胞外信号调节激酶的激活。这种逆转显示背腹侧的进展，这样，到36小时，细胞外信号调节激酶的激活几乎仅限于髓核，在野生型小鼠。多巴胺D-1受体激活的细胞外信号调节激酶在多巴胺缺乏的小鼠慢性左旋多巴治疗后的逆转表明，缺乏多巴胺，而不是缺乏其他因素分泌的多巴胺能神经元，是负责多巴胺超敏感性。(c)2005由Elsevier Ltd代表IBRO出版。
Lesions of dopaminergic nigrostriatal neurons cause supersensitivity to dopamine in the striatum. Previous work has shown that such supersensitivity, an important aspect of rodent models of Parkinson's disease, is associated with anatomically abnormal patterns in the activation of extracellular signal-regulated kinase. After lesions of dopaminergic neurons, dopamine D-1-receptor agonists activate extracellular signal-regulated kinase in the dorsal striaturn, something not observed in intact animals. Here we used a more selective method of dopamine depletion. Dopamine-deficient mice, in which the tyrosine hydroxylase gene is specifically inactivated in dopaminergic neurons, were used to investigate dopamine D-1-receptor-mediated activation of extracellular signal-regulated kinase. In wild-type mice, acute treatment with a dopamine D,-receptor agonist results in activation of extracellular signal-regulated kinase in the nucleus accumbens without activation in the dorsal striaturn. In contrast, in dopamine-deficient mice, dopamine D-1-receptor-agonist treatment results in activation of extracellular signal-regulated kinase not only in the nucleus accumbens, but also throughout most of the dorsal striaturn. Chronic replacement of dopamine by repeated injection of L-DOPA for 36 h reverses this supersensitive extracellular signal-regulated kinase activation. This reversal displays a dorsal to ventral progression such that, by 36 h, extracellular signal-regulated kinase activation is virtually restricted to the nucleus accumbens, as in wild-type mice. The reversal of dopamine D-1-receptor activation of extracellular signal-regulated kinase in dopamine-deficient mice following chronic L-DOPA treatment shows that the lack of dopamine, rather than absence of other factors secreted from dopaminergic neurons, is responsible for dopamine supersensitivity. (c) 2005 Published by Elsevier Ltd on behalf of IBRO.