Differences between dorsal and ventral striatum in Drd1a dopamine receptor coupling of dopamine- and cAMP-regulated phosphoprotein-32 to activation of extracellular signal-regulated kinase.
Differences between dorsal and ventral striatum in Drd1a dopamine receptor coupling of dopamine- and cAMP-regulated phosphoprotein-32 to activation of extracellular signal-regulated kinase.
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DOI：
10.1523/jneurosci.3952-07.2008
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发表时间：
2008-07-09
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影响因子：
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通讯作者：
Worley P
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文献类型：
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作者：
Gerfen CR;Paletzki R;Worley P
多巴胺受体信号传导表现出突出的可塑性，这对成瘾和运动障碍的发病机制都很重要。激活多巴胺D1受体（drd 1a）的精神活性兴奋剂诱导中脑核和腹侧纹状体神经元中ERK 1/2的快速磷酸化和激活。已知这种反应依赖于磷酸酶抑制剂DARPP-32，并且似乎对导致成瘾的drd 1a反应的致敏至关重要。如在帕金森病（PD）模型中一样，纹状体的多巴胺输入的损失也导致对多巴胺激动剂的反应的敏化，这通过背侧纹状体中ERK 1/2的活化增加来表现。在这里，我们测试DARPP-32是否是PD模型中drd 1a反应致敏所必需的。在正常的背侧纹状体中，存在最小的drd 1a介导的ERK 1/2激活，然而，在PD模型中存在稳健的drd 1a介导的ERK 1/2激活。在野生型和DARPP-32基因敲除小鼠中，drd 1a在整个多巴胺耗尽的纹状体中强烈诱导pERK 1/2。这些发现表明，与PD相关的drd 1a致敏作用是通过一种不需要DARPP-32的新机制发生的。
Dopamine receptor signaling exhibits prominent plasticity that is important for the pathogenesis of both addictive and movement disorders. Psychoactive stimulants that activate the dopamine D1 receptor (drd1a) induce the rapid phosphorylation and activation of ERK1/2 in neurons of the nucleus accumbens and ventral striatum. This response is known to be dependent on the phosphatase inhibitor, DARPP-32 and appears critical for the sensitization of drd1a responses that contributes to addiction. Loss of dopamine input to the striatum, as in models of Parkinson's disease (PD), also results in a sensitization of responses to dopamine agonists that is manifest by increased activation of ERK1/2 in the dorsal striatum. Here we test if DARPP-32 is required for sensitization of drd1a responses in a PD model. In the normal dorsal striatum, there is minimal drd1a-mediated activation of ERK1/2, however, in the PD model there is robust drd1a-mediated activation of ERK1/2. In both wild-type and DARPP-32 knockout mice, drd1a robustly induces pERK1/2 throughout the dopamine-depleted striatum. These findings indicate that drd1a sensitization relevant for PD occurs by a novel mechanism that does not require DARPP-32.