DEVELOPMENTAL REFRACTORINESS

甲基苯丙胺（METH）对多巴胺能神经元造成长期损害，青少年较少 比年轻的成年大鼠更敏感。此外，从青春期开始用甲基苯丙胺预处理， 在成年期给予METH时引起的持续性多巴胺能缺陷。机制 这些“抗性”现象的根本原因仍有待阐明。一个重要的假设是 节目项目是在早期发生的事件（即，< 8 h）治疗后（ 在此称为“阶段1”）和之后（即，处理后24 - 72小时，本文称为“阶段2”）， 造成这样的伤害因此，本项目将检验“第2阶段”事件与下列事件有关的假设： 细胞内DA管理对于由METH引起的持续性多巴胺能缺陷至关重要， 并且这些事件在青春期大鼠和用METH治疗的大鼠中均不存在。 发展“这将通过调查来检验： 1)发展的影响，以及青春期METH治疗对表达的影响， 在“阶段2”期间发生的甲基苯丙胺诱导的效应，包括调节 神经元内DA分布和反应性物质的形成。为了完整性，神经胶质细胞活化将是 评估也是。 2)如果靶向抑制“阶段2”事件防止了由以下引起的持续性多巴胺能缺陷： METH.在“第1阶段”开始后进行药理学操作，以确定这些药物是否 治疗预防由METH引起的“2期”事件和/或长期多巴胺能损伤。 3)发展的影响，以及青春期METH治疗对表达的影响， 在“阶段1”期间发生的MET诱导效应，包括对以下方面的效应：1）囊泡单胺 转运蛋白-2; 2）DA转运蛋白和3）反应性物质形成。这一点即使在 虽然本项目的重点是“阶段2”，因为假设“阶段1”中发生的因素 有助于表达。 重要的是，其他几个因素也导致了METH引起的长期缺陷，这些因素是METH治疗的重点。 此PO 1应用程序中的其他项目。本项目将侧重于具体的“第1阶段”和“第2阶段”因素 包括上文所述的那些。所得数据将用于为项目#2和#3中的研究提供信息 关于潜在的研究对象，反之亦然。相似和不相似机制的识别 这些项目中的因素不仅将提供对与甲基苯丙胺诱导的神经毒性有关的问题的深入了解， 还包括涉及多巴胺能神经元的变性疾病，例如帕金森病。

Methamphetamine (METH) causes long-term damage to dopaminergic neurons, with adolescent being less susceptible than young adult rats. Further, pretreatment with METH, beginning in adolescence, prevents the persistent dopaminergic deficits caused when METH is administered during adulthood. Mechanisms underlying these "resistance" phenomena remain to be elucidated. One overarching hypothesis of this program project is that events occurring during the early hours (i.e., < 8 h) after treatment (a period referred to herein as "stage 1") and later (i.e., 24 - 72 h after treatment, referred to herein as "stage 2") are both necessary to elicit this damage. Thus, this project will test the hypothesis that "stage 2" events related to intracellular DA management are critical for the persistent dopaminergic deficits caused by METH, and that these events are absent in both adolescent rats and those treated with METH during development." This will be tested by investigating: 1) the impact of development, and of METH treatment during adolescence, on the expression of METH-induced effects occurring during "stage 2" including disruption of factors regulating intraneuronal DA distribution and reactive species formation. For completeness, glial cell activation will be assessed as well. 2) if targeted inhibition of "stage 2" events prevents the persistent dopaminergic deficits caused by METH. Pharmacological manipulations will be performed after the onset of "stage 1" to determine if these treatments prevent "stage 2" events and/or the long-term dopaminergic damage caused by METH. 3) the impact of development, and of METH treatment during adolescence, on the expression of METH-induced effects occurring during "stage 1" including effects on: 1) the vesicular monoamine transporter-2; 2) the DA transporter and 3) reactive species formation. This will be accomplished even though the focus of this Project is "stage 2," as it is hypothesized that the factors occurring in "stage 1" contribute to its expression. Importantly, several other factors contribute to the long-term deficits caused by METH and are focuses of other projects in this PO1 application. This Project will focus on specific "stage 1" and "stage 2" factors including those delineated above. Resulting data will be used to inform studies in Projects #2 and #3 regarding potential targets of study, and visa versa. Identification of similar and dissimilar mechanistic factors among the projects will provide insight into not only issues related to METH-induced neurotoxicity, but also degenerative disorders involving dopaminergic neurons such as Parkinson's disease.