"Differential Effects of Methamphetamine and Cocaine"

描述（由申请人提供）：由于这种强效精神兴奋剂的严重持续性精神症状和令人不安的社会影响，在这个国家持续滥用甲基苯丙胺（冰毒）尤其令人不安。为了更好地处理冰毒成瘾的后果，阐明其短期和长期影响的相关机制是很重要的。我们和其他人研究的两个重要问题与目前的建议特别相关：第一，甲基苯丙胺在某些情况下（但不是所有情况）导致纹状体多巴胺系统持续缺陷（神经毒性）的特性；第二，对青少年动物与成年动物对甲基苯丙胺治疗的独特反应的相关观察。本修订提案的总体目标是阐明皮层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）在不同难解条件下的不同易损性有关。因此，本提案中的研究基于我们和其他人的观察，即与甲基苯丙胺诱导的持续纹状体DA缺陷相关的因素根据其与药物暴露的时间关系分为两个阶段（即阶段1=0-8小时，阶段2=24-72小时）。我们将通过验证流行的假设来实现总体目标，即“在纹状体DA系统中，在第1阶段发生的事件以及在第2阶段发生的事件对于甲基冰毒诱导毒性的表达是必要的，本项目研究的甲基冰毒抗性模型以不同的方式干扰了必要的事件。”这一假设将通过检查甲基苯丙胺耐药性模型中甲基苯丙胺诱导的第1和第2阶段的表达变化及其潜在机制来验证：(i)青春期大鼠（项目#1-“发育难耐性”，项目主任是Annette Fleckenstein博士）；（ii）用神经毒性甲基安非他明治疗预处理成年大鼠（项目#2-“成人病变诱发的难治性”，项目主任是Kristen Keefe博士）；（iii）先前暴露于由逐渐增加的甲基安非他明剂量引起的暂时耐受性的大鼠（项目#3-“耐受性相关的可逆性难治性”，项目主管是Diana Wilkins博士）。预计阐明这3种难治性模型的机制将为以下问题提供信息：(i)青少年药物滥用脆弱性；在青少年发育期间使用甲基苯丙胺的影响；（iii）冰毒相关神经毒性在成年期的持续影响。

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