Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse/National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland, United States of America.
PLoS One. 2010 Dec 13;5(12):e15643. doi: 10.1371/journal.pone.0015643.
Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle are used extensively as a model of Parkinson's disease. The present experiments sought to identify genes that were affected in the dopamine (DA)-denervated striatum after 6-hydroxydopamine-induced destruction of the nigrostriatal dopaminergic pathway in the rat. We also examined whether a single injection of methamphetamine (METH) (2.5 mg/kg) known to cause changes in gene expression in the normally DA-innervated striatum could still influence striatal gene expression in the absence of DA. Unilateral injections of 6-hydroxydopamine into the medial forebrain bundle resulted in METH-induced rotational behaviors ipsilateral to the lesioned side and total striatal DA depletion on the lesioned side. This injection also caused decrease in striatal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels. DA depletion was associated with increases in 5-HIAA/5-HT ratios that were potentiated by the METH injection. Microarray analyses revealed changes (±1.7-fold, p<0.025) in the expression of 67 genes on the lesioned side in comparison to the intact side of the saline-treated hemiparkinsonian animals. These include follistatin, neuromedin U, and tachykinin 2 which were up-regulated. METH administration caused increases in the expression of c-fos, Egr1, and Nor-1 on the intact side. On the DA-depleted side, METH administration also increased the expression of 61 genes including Pdgf-d and Cox-2. There were METH-induced changes in 16 genes that were common in the DA-innervated and DA-depleted sides. These include c-fos and Nor-1 which show greater changes on the normal DA side. Thus, the present study documents, for the first time, that METH mediated DA-independent changes in the levels of transcripts of several genes in the DA-denervated striatum. Our results also implicate 5-HT as a potential player in these METH-induced alterations in gene expression because the METH injection also caused significant increases in 5-HIAA/5-HT ratios on the DA-depleted side.
单侧注射 6-羟多巴胺到内侧前脑束被广泛用于帕金森病的模型。本实验试图确定在大鼠黑质纹状体多巴胺能通路被 6-羟多巴胺破坏后，多巴胺（DA）去神经纹状体中的受影响的基因。我们还检查了单次注射（2.5mg/kg）甲基苯丙胺（METH）是否仍然可以在没有 DA 的情况下影响正常 DA 支配的纹状体中的纹状体基因表达。单侧注射 6-羟多巴胺到内侧前脑束导致 METH 诱导的对侧旋转行为和对侧纹状体 DA 耗竭。该注射还导致纹状体 5-羟色胺（5-HT）和 5-羟吲哚乙酸（5-HIAA）水平降低。DA 耗竭与 METH 注射增强的 5-HIAA/5-HT 比值增加有关。微阵列分析显示，与盐水处理的半帕金森动物的完整侧相比，损伤侧的 67 个基因的表达发生变化（±1.7 倍，p<0.025）。这些包括滤泡抑素、神经调节素 U 和速激肽 2，它们被上调。METH 给药导致完整侧的 c-fos、Egr1 和 Nor-1 的表达增加。在 DA 耗竭侧，METH 给药还增加了包括 Pdgf-d 和 Cox-2 在内的 61 个基因的表达。在 DA 支配和 DA 耗竭侧均有 METH 诱导的 16 个基因的变化。这些包括 c-fos 和 Nor-1，它们在正常 DA 侧显示出更大的变化。因此，本研究首次记录了 METH 介导的在 DA 去神经纹状体中几个基因的转录物水平的 DA 非依赖性变化。我们的结果还表明 5-HT 作为这些 METH 诱导的基因表达改变的潜在参与者，因为 METH 注射还导致 DA 耗竭侧 5-HIAA/5-HT 比值显著增加。
