TOLERANCE-RELATED REVERSIBLE REFRACTORINESS

甲基苯丙胺[冰毒]是滥用的强效兴奋剂，具有高度成瘾性和长期服药的特点 这种药物的不良反应会导致对冰毒的耐受性。这项提议的目的是澄清潜在的 冰毒耐受性机制：对多个大剂量的毒性产生一过性抵抗 行政管理。类似的机制可能是青春期啮齿动物对冰毒产生抵抗力的基础 毒性。已经确定了几个因素，似乎与#年持续的DA赤字密切相关 由多次注射高剂量冰毒引起的纹状体。利用精选的证据 标志物(例如，多巴胺转运体[DAT]、囊泡单胺转运体-2[VMAT-2]功能、DAT 复合体形成、胶质细胞反应、热休克蛋白表达和氮依赖反应 物种生产)，这些因素在时间上似乎分为两大类 与冰毒接触有关。其中包括：冰毒后持续约8小时的“第一阶段” 治疗，以及2)似乎发生在24-48小时内的“第二阶段”。我们的研究将考察 总体假设：暴露于不断增加的冰毒剂量会导致暂时性的机制改变 这触发了阶段1之后的阶段2的表达，从而防止了冰毒中毒的发生。 以下具体目的旨在证明或反驳这一假设：(I)：确定影响 以及诱导耐受的甲氧基甲胺对黑质纹状体DA系统本身的时间分布，以及 阶段1和2对随后多次大剂量注射冰毒的挑战的反应；(2) 测定诱导耐受性冰毒预处理对氧化连接蛋白表达的影响 系统本身，以及它们在阶段1和阶段2对随后的多次高剂量挑战的反应 冰毒管理局。(ILL)确定诱导耐受的冰毒预处理对DA的影响， 谷氨酸和糖皮质激素系统本身，以及它们在阶段1和阶段2对后续挑战的反应 多次大剂量注射冰毒。从每一项实验中获得的数据 明确的目标将增加我们对与耐受性形成有关的神经化学的理解 为了冰毒。此外，结合对青春期动物的实验，这些数据将提供对 与青少年人口的药物滥用脆弱性有关的问题。

The potent stimulant of abuse, methamphetamine [METH] is highly addictive and chronic administration of this drug can lead to tolerance to METH's effects. The goal of this proposal to elucidate the underlying mechanisms of tolerance to METH that provide a transient resistance to toxicity resultant to multiple highdose administration. Similar mechanisms may underlie the resistance of adolescent rodents to METH toxicity. Several factors have been identified that appear to be closely linked to the persistent DA deficits in the striatum caused by multiple administrations of high doses of METH. Utilizing evidence from selected markers (e.g. the dopamine transporter [DAT], vesicular monoamine transporter-2 [VMAT-2] function, DAT complex formation, glial cell reactions, heat shock protein expression, and nitrogen-dependent reactive species production), these factors appear to fall into two broad classifications with respect to their temporal relationship to METH exposure. These include: a "first stage" that persists for ~ 8 hours after the METH treatment, and 2) a "second stage" that appears to occur from ~24-48 hrs. Our studies will examine the overall hypothesis: Exposure to escalating doses of METH leads to a temporary alteration in mechanisms that trigger Stage 2 after Stage 1 expression, thereby preventing occurrence of METH-induced toxicity. The following Specific Aims are designed to prove or disprove this hypothesis: (I): Determine the effects and temporal profile of a tolerance-inducing METH pretreatment on nigrostriatal DA systems per se, and the response of Stages 1 and 2 to subsequent challenge with multiple high-dose METH administrations; (II) Determine the effects of a tolerance-inducing METH pretreatment on the expression of oxidatively linked systems per se, and their response in Stages 1 and 2 to subsequent challenge with multiple high-dose METH administrations. (Ill) Determine the effects of a tolerance-inducing METH pretreatment on DA, glutamate and glucocorticoid systems per se, and their response in Stages 1 and 2 to subsequent challenge with multiple high-dose METH administrations. The data obtained from the experiments in each of these Specific Aims will increase our understanding of the neurochemistry involved in the development of tolerance to METH. In addition, together with experiments in adolescent animals, these data will provide insight into issues related to drug abuse vulnerability in the adolescent population.