"Differential Effects of Methamphetamine and Cocaine"

描述(申请人提供)：在这个国家继续滥用甲基苯丙胺(冰毒)尤其令人担忧，因为这种强大的精神刺激剂具有严重的持续性精神症状和令人不安的社会影响。为了更好地处理冰毒成瘾的后果，重要的是阐明与其短期和长期影响相关的机制。我们和其他人研究的两个与本提案特别相关的重要问题是：第一，冰毒在某些情况下(但不是所有情况下)导致纹状体多巴胺系统持续缺陷的特性；第二，青少年与成年动物对冰毒治疗的独特反应的相关观察。这项修订建议的总体目标是阐明皮质下单胺系统对冰毒的神经毒性反应，因为它与纹状体多巴胺(DA)在不同难治条件下的不同脆弱性有关。因此，这项建议中的研究是基于我们和其他人的观察，即与冰毒诱导的持续性纹状体DA缺陷有关的因素根据它们与药物暴露的时间关系分为两个阶段(即阶段1=0-8h和阶段2=24-72h)。我们将通过检验盛行的假设来实现总体目标，该假说是：“在第一阶段和第二阶段发生的事件对于纹状体DA系统中冰毒的表达是必要的，并且本计划项目中要研究的冰毒抗性模型以不同的方式干扰必要的事件。”这一假说将通过检测以下冰毒抵抗模型中冰毒诱导的阶段1和2的表达的变化和潜在的机制来检验：(I)青春期大鼠(项目#1-“发育性难治性”，项目主任是Annette Fleckenstein博士)；(Ii)用神经毒性冰毒治疗预处理的成年大鼠(项目#2-“成人病变诱导的难治性”，项目主任是Kristen Keefe博士)；以及(Iii)先前暴露于由递增冰毒剂量引起的暂时性耐受性的大鼠(项目#3-“与耐受性相关的可逆耐受性”，项目主任是戴安娜·威尔金斯博士)。预计对这3个难治模型的机制的阐明将为以下问题提供信息：(1)青少年药物滥用的脆弱性；(2)青少年发育期间使用冰毒的影响；以及(3)成年期与冰毒有关的神经毒性的持续影响。 计划项目的特点

DESCRIPTION (provided by applicant): The continued abuse of methamphetamine (METH) in this country is particularly troubling because of the severe persistent psychiatric symptoms and disturbing social impact of this potent psychostimulant. In order to better deal with the consequences of METH addiction, it is important to elucidate the mechanisms associated with its short- and long-term effects. Two important issues we and others have researched that are particularly germane to the present proposal are: first, the property of METH to cause persistent deficits in striatal dopamine systems (neurotoxicity) under some, but not all, conditions: and second, the related observation of a unique response to METH treatment by adolescent versus adult animals. The overall objective of this revised proposal is to elucidate the neurotoxic responses of subcortical monoamine systems to METH, as it relates to the differential vulnerability of striatal dopamine (DA) under varying refractory conditions. Thus, studies in this proposal are based on our and others' observations that factors linked to the METH-induced persistent striatal DA deficits fall into two stages based on their temporal relationship to drug exposure (i.e., Stage 1=0-8 h and Stage 2=24-72 h). We will achieve the overall objective by testing the prevailing hypothesis that "events occurring during Stage 1 followed by those of Stage 2 are necessary for the expression of METH-induced toxicity in striatal DA systems and the models of resistance to METH toxicity to be studied in this Program Project interfere with the requisite events in distinct ways." This hypothesis will be tested by examining alterations in the expressions of METH-induced Stages 1 and 2, and underlying mechanisms, in the following models of METH resistance: (i) adolescent rats (project #1- "Developmental Refractoriness," project director is Dr. Annette Fleckenstein); (ii) adult rats pretreated with a neurotoxic-METH treatment (project #2-"Lesion-induced Refractoriness in Adults," project director is Dr. Kristen Keefe); and (iii) rats previously exposed to a temporary tolerance caused by incrementally increasing METH doses (project #3-"tolerance-related Reversible Refractoriness," project director is Dr. Diana Wilkins). It is anticipated that elucidation of mechanisms for these 3 refractory models will inform issues such as: (i) adolescent drug abuse vulnerability; (ii) impact of METH use during adolescent development; and (iii) the persistent impact of METH-related neurotoxicity during adulthood. PROGRAM PROJECT CHARACTERISTICS