PDF(Pubmed)
Abstract：
In rodents with unilateral ablation of neurons supplying dopamine to the striatum, chronic treatment with the dopamine precursor L-DOPA induces a progressive increase of behavioral responses, a process known as behavioral sensitization. This sensitization is blunted in arrestin-3 knockout mice. Using virus-mediated gene delivery to the dopamine-depleted striatum of these mice, we find that the restoration of arrestin-3 fully rescues behavioral sensitization, whereas its mutant defective in c-Jun N-terminal kinase (JNK) activation does not. A 25-residue arrestin-3-derived peptide that facilitates JNK3 activation in cells, expressed ubiquitously or selectively in direct pathway striatal neurons, also fully rescues sensitization, whereas an inactive homologous arrestin-2-derived peptide does not. Behavioral rescue is accompanied by the restoration of JNK3 activity, as reflected by JNK-dependent phosphorylation of the transcription factor c-Jun in the dopamine-depleted striatum. Thus, arrestin-3-assisted JNK3 activation in direct pathway neurons is a critical element of the molecular mechanism underlying sensitization upon dopamine depletion and chronic L-DOPA treatment.
摘要：
在向纹状体提供多巴胺的神经元单侧消融的啮齿动物中，多巴胺前体L-DOPA的慢性治疗诱导行为反应的进行性增加，一个被称为行为敏化的过程。这种致敏作用在抑制蛋白-3敲除小鼠中减弱。使用病毒介导的基因递送到这些小鼠的多巴胺耗尽的纹状体，我们发现arrestin-3的恢复完全挽救了行为敏感性，而其突变体在c-JunN末端激酶（JNK）激活方面没有缺陷。一种25个残基的抑制蛋白-3衍生肽，可促进JNK3在细胞中的活化，在直接途径纹状体神经元中普遍或选择性表达，也充分挽救了敏感性，而无活性的同源抑制蛋白2衍生肽则没有。行为拯救伴随着JNK3活性的恢复，正如多巴胺耗竭纹状体中转录因子c-Jun的JNK依赖性磷酸化所反映的那样。因此，抑制蛋白-3辅助JNK3在直接途径神经元中的激活是多巴胺消耗和慢性L-DOPA治疗后致敏的分子机制的关键要素。
