DEVELOPMENTAL REFRACTORINESS

甲基苯丙胺(冰毒)对多巴胺能神经元造成长期损害，青少年损害较小 比年轻的成年大鼠更易受影响。此外，从青春期开始的冰毒预处理可以防止 成年期服用冰毒时造成的持续性多巴胺能缺陷。机制 这些“抵抗”现象背后的原因仍有待阐明。关于这一点的一个重要假设 方案项目是指在治疗后的早期(即8小时)内发生的事件(所指期间 在此被称为“阶段1”)和之后(即，在治疗后24-72小时，在这里被称为“阶段2”)都是 造成这种损害是必要的。因此，该项目将检验这样一种假设：“第二阶段”事件与 细胞内DA管理对于冰毒引起的持续性多巴胺能缺陷至关重要， 这些事件在青春期大鼠和服用冰毒的大鼠中都没有 这将通过以下调查进行测试： 1)发育和青春期冰毒治疗对基因表达的影响 在“第二阶段”发生的冰毒效应，包括调节因子的中断 神经元内DA的分布和活性物种的形成。为了完整，神经胶质细胞的激活将是 也进行了评估。 2)如果有针对性地抑制“第二阶段”事件，防止由以下原因引起的持续性多巴胺能缺陷 冰毒。在“第一阶段”开始后，将进行药物操作，以确定这些 治疗可以防止“第二阶段”事件和/或冰毒引起的长期多巴胺能损伤。 3)发育和青春期冰毒治疗对基因表达的影响 冰毒作用发生在“阶段1”，包括对：1)囊泡单胺的影响 转运体-2)DA转运体和3)活性物种的形成。这一点甚至可以实现 虽然本项目的重点是“第二阶段”，因为假设发生在“第一阶段”的因素 为其表达做出贡献。 重要的是，其他几个因素导致了冰毒造成的长期赤字，这些因素是 此PO1应用程序中的其他项目。本项目将侧重于具体的“第一阶段”和“第二阶段”因素 包括上面描述的那些。所产生的数据将用于为项目2和3中的研究提供信息 关于潜在的研究对象，反之亦然。相似机构与不同机构的识别 这些项目中的因素将不仅提供对与冰毒引起的神经毒性相关的问题的洞察， 但也包括涉及多巴胺能神经元的退行性疾病，如帕金森氏症。

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.