Methamphetamine preconditioning alters midbrain transcriptional responses to methamphetamine-induced injury in the rat striatum.
Methamphetamine preconditioning alters midbrain transcriptional responses to methamphetamine-induced injury in the rat striatum.
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DOI：
10.1371/journal.pone.0007812
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发表时间：
2009-11-12
期刊：
影响因子：
3.7
通讯作者：
Hodges AB
中科院分区：
文献类型：
--
作者：
Cadet JL;McCoy MT;Cai NS;Krasnova IN;Ladenheim B;Beauvais G;Wilson N;Wood W;Becker KG;Hodges AB
甲基苯丙胺是一种对哺乳动物大脑有神经毒性的非法药物。许多研究表明，在短时间内接触中到大剂量冰毒的动物大脑中的多巴胺和5-羟色胺水平显著下降。相比之下，反复注射小剂量的无毒药物，然后挑战有毒的冰毒剂量，可以有效地防止单胺消耗。目前的研究是为了测试重复注射药物的可能性，可能伴随着转录变化，导致黑质纹状体多巴胺能系统对冰毒不耐药。我们的结果证实，冰毒预适应对冰毒诱导的纹状体多巴胺耗竭有显著的保护作用。此外，冰毒预适应的存在和不存在与其表达受到有毒冰毒挑战影响的基因的特性显著不同有关。定量聚合酶链式反应证实了冰毒诱导的感兴趣基因的变化，并确定了在冰毒预适应存在的情况下，受有毒冰毒挑战的不同影响的其他基因。这些基因包括小热休克27 kD 27蛋白2(HspB2)、促甲状腺激素释放激素(TRH)、脑源性神经营养因子(BDNF)、c-fos，以及一些编码抗氧化蛋白的蛋白，包括CuZn超氧化物歧化酶(CuZnSOD)、谷胱甘肽过氧化物酶(GPx)-1和血红素加氧酶-1(Hmox-1)。这些观察结果在一定程度上与在致死性缺血损伤模型中报告的转录变化是一致的，这些模型在缺血或药物预适应之前。我们的发现表明，多个分子通路可能协同工作，以保护黑质纹状体多巴胺能通路免受有毒精神刺激剂的有害影响。对这些基因调控的分子和细胞通路的进一步分析应该有助于对反复接触滥用药物时大脑的神经适应潜力提供一些洞察。
Methamphetamine (METH) is an illicit drug which is neurotoxic to the mammalian brain. Numerous studies have revealed significant decreases in dopamine and serotonin levels in the brains of animals exposed to moderate-to-large METH doses given within short intervals of time. In contrast, repeated injections of small nontoxic doses of the drug followed by a challenge with toxic METH doses afford significant protection against monoamine depletion. The present study was undertaken to test the possibility that repeated injections of the drug might be accompanied by transcriptional changes involved in rendering the nigrostriatal dopaminergic system refractory to METH toxicity. Our results confirm that METH preconditioning can provide significant protection against METH-induced striatal dopamine depletion. In addition, the presence and absence of METH preconditioning were associated with substantial differences in the identity of the genes whose expression was affected by a toxic METH challenge. Quantitative PCR confirmed METH-induced changes in genes of interest and identified additional genes that were differentially impacted by the toxic METH challenge in the presence of METH preconditioning. These genes include small heat shock 27 kD 27 protein 2 (HspB2), thyrotropin-releasing hormone (TRH), brain derived neurotrophic factor (BDNF), c-fos, and some encoding antioxidant proteins including CuZn superoxide dismutase (CuZnSOD), glutathione peroxidase (GPx)-1, and heme oxygenase-1 (Hmox-1). These observations are consistent, in part, with the transcriptional alterations reported in models of lethal ischemic injuries which are preceded by ischemic or pharmacological preconditioning. Our findings suggest that multiple molecular pathways might work in tandem to protect the nigrostriatal dopaminergic pathway against the deleterious effects of the toxic psychostimulant. Further analysis of the molecular and cellular pathways regulated by these genes should help to provide some insight into the neuroadaptive potentials of the brain when repeatedly exposed to drugs of abuse.
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影响因子：
5.3
作者：
Boger, Heather A.;Middaugh, Lawrence D.;McGinty, Jacqueline F.
通讯作者：
McGinty, Jacqueline F.
影响因子：
5
作者：
Danaceau, Jonathan P.;Deering, Cassandra E.;Wilkins, Diana G.
通讯作者：
Wilkins, Diana G.
DOI：
10.1016/j.biocel.2004.09.009
发表时间：
2005-05-01
影响因子：
4
作者：
Chinta, SJ;Andersen, JK
通讯作者：
Andersen, JK
DOI：
10.1073/pnas.0401827101
发表时间：
2004-07-13
影响因子：
11.1
作者：
Bruce, AW;Donaldson, IJ;Buckley, NJ
通讯作者：
Buckley, NJ
影响因子：
6
作者：
Chang, Linda;Alicata, Daniel;Volkow, Nora
通讯作者：
Volkow, Nora