Chronic alterations in dopaminergic neurotransmission produce a persistent elevation of Delta FosB-like protein(s) in both the rodent and primate striatum
Chronic alterations in dopaminergic neurotransmission produce a persistent elevation of Delta FosB-like protein(s) in both the rodent and primate striatum
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DOI：
10.1111/j.1460-9568.1996.tb01220.x
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发表时间：
1996-02-01
影响因子：
3.4
通讯作者：
Robertson, GS
中科院分区：
文献类型：
--
作者：
Doucet, JP;Nakabeppu, Y;Robertson, GS
使用识别立即早期基因的fos家族的所有已知成员的产物的抗体，证明了通过内侧前脑束的6-羟基多巴胺（6-OHDA）损伤对黑质纹状体通路的破坏产生纹状体中Fos样免疫反应性的延长（>3个月）升高。使用逆行追踪技术，我们以前已经表明，这种增加Fos样免疫反应主要位于纹状体神经元的项目苍白球。在本研究中，对6-OHDA损伤大鼠的完整和去神经纹状体的核提取物进行Western印迹，以确定导致这种增加的Fos免疫反应性蛋白的性质。大约6周后，6-OHDA病变，两个Fos相关抗原的表达与表观分子量为43和45 kDa的增强在失神经支配的纹状体。长期氟哌啶醇管理也选择性地升高这些Fos相关抗原的表达，表明其诱导后多巴胺能去神经介导的去样多巴胺受体的激活减少。Western印迹免疫染色使用的抗体，它可以识别N-末端的FosB表明，43和45 kDa的Fos相关抗原诱导多巴胺能神经和慢性氟哌啶醇管理可能与截断的FosB称为三角洲FosB。与这一建议相一致，逆行追踪实验证实，三角洲FosB样免疫反应性在去传入纹状体主要位于striatopallidal神经元。凝胶位移实验表明，在去神经纹状体中升高的AP-1结合活性含有FosB样蛋白，表明增强的Delta FosB水平可能介导延长的多巴胺耗竭对纹状体苍白球神经元中AP-1调节基因的一些影响。与此相反，慢性给药的D1样受体激动剂CY 208-243 6-OHDA损伤大鼠显着增强三角洲FosB样免疫反应在纹状体神经元投射到黑质。Western blot免疫染色显示，三角洲FosB和，在较小程度上，FosB升高慢性D1样激动剂管理。定量逆转录-聚合酶链反应和核糖核酸酶保护试验表明，三角洲fosB mRNA水平大幅提高，在去神经纹状体慢性D1样激动剂管理。最后，我们研究了长期给予D1样和D2样多巴胺受体激动剂对1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）帕金森病灵长类动物模型纹状体Delta FosB表达的影响。在因MPTP而患帕金森病的猴子中，Delta FosB样蛋白略有增加，而慢性D1样激动剂给药引起的运动障碍的发展伴随着Delta FosB样蛋白的大幅增加。相比之下，长效D2样激动剂卡麦角林的给药（缓解帕金森病症状而不产生运动障碍）使Delta FosB水平降至接近正常。总之，这些结果表明，多巴胺能神经传递的慢性改变在啮齿类和灵长类纹状体中产生了Delta FosB样蛋白的持续升高。
Using an antibody that recognizes the products of all known members of the fos family of immediate early genes, it was demonstrated that destruction of the nigrostriatal pathway by 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle produces a prolonged (>3 months) elevation of Fos-like immunoreactivity in the striatum. Using retrograde tract tracing techniques, we have previously shown that this increase in Fos-like immunoreactivity is located predominantly in striatal neurons that project to the globus pallidus. In the present study, Western blots were performed on nuclear extracts from the intact and denervated striatum of 6-OHDA-lesioned rats to determine the nature of Fos-immunoreactive protein(s) responsible for this increase. Approximately 6 weeks after the 6-OHDA lesion, expression of two Fos-related antigens with apparent molecular masses of 43 and 45 kDa was enhanced in the denervated striatum. Chronic haloperidol administration also selectively elevated expression of these Fos-related antigens, suggesting that their induction after dopaminergic denervation is mediated by reduced activation of De-like dopamine receptors. Western blot immunostaining using an antibody which recognizes the N-terminus of FosB indicated that the 43 and 45 kDa Fos-related antigens induced by dopaminergic denervation and chronic haloperidol administration may be related to a truncated from of FosB known as Delta FosB. Consistent with this proposal, retrograde tracing experiments confirmed that Delta FosB-like immunoreactivity in the deafferented striatum was located predominantly in striatopallidal neurons. Gel shift experiments demonstrated that elevated AP-1 binding activity in denervated striata contained FosB-like protein(s), suggesting that enhanced Delta FosB levels may mediate some of the effects of prolonged dopamine depletion on AP-l-regulated genes in striatopallidal neurons. In contrast, chronic administration of the D1-like receptor agonist CY 208-243 to 6-OHDA-lesioned rats dramatically enhanced Delta FosB-like immunoreactivity in striatal neurons projecting to the substantia nigra. Western blot immunostaining revealed that Delta FosB and, to a lesser extent, FosB are elevated by chronic D1-like agonist administration. Both the quantitative reverse transcriptase-polymerase chain reaction and the ribonuclease protection assay demonstrated that Delta fosB mRNA levels were substantially enhanced in the denervated striatum by chronic D1-like agonist administration. Lastly, we examined the effects of chronic administration of D1-like and D2-like dopamine receptor agonists on striatal Delta FosB expression in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson's disease. In monkeys rendered Parkinsonian by MPTP, there was a modest increase in Delta FosB-like protein(s), while the development of dyskinesia produced by chronic D1-like agonist administration was accompanied by large increases in Delta FosB-like protein(s). In contrast, administration of the long-acting D2-like agonist cabergoline, which alleviated Parkinsonian symptoms without producing dyskinesia reduced Delta FosB levels to near normal. Taken together, these results demonstrate that chronic alterations in dopaminergic neurotransmission produce a persistent elevation of Delta FosB-like protein(s) in both the rodent and primate striatum.