"Differential Effects of Methamphetamine and Cocaine"

描述（由申请人提供）：甲基苯丙胺（METH）在这个国家的持续滥用特别令人不安，因为这种强效精神兴奋剂严重持续的精神症状和令人不安的社会影响。为了更好地处理METH成瘾的后果，重要的是要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重要问题与本提案特别密切相关：第一，METH在某些（但不是所有）条件下导致纹状体多巴胺系统持续缺陷（神经毒性）的特性;第二，青春期与成年动物对METH治疗的独特反应的相关观察。这个修订后的建议的总体目标是阐明神经毒性反应的皮质下单胺系统甲基，因为它涉及到不同的脆弱性纹状体多巴胺（DA）在不同的难治性条件下。因此，本提案中的研究是基于我们和其他人的观察，即与MET诱导的持续性纹状体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 h，阶段2=24-72 h）。我们将通过检验流行的假设来实现总体目标，即“在第1阶段发生的事件，随后是第2阶段发生的事件，对于纹状体DA系统中的METH诱导毒性的表达是必要的，并且本计划项目中要研究的对METH毒性的抗性模型以不同的方式干扰必要的事件。“这一假设将通过检查以下METH耐药模型中METH诱导的第1和第2阶段表达的变化及其潜在机制来检验：（项目#1-“发育不应性”，项目主任是Annette Fleckenstein博士）;（ii）用神经毒性-METH处理预处理的成年大鼠（项目#2-“成人病变诱导的不应性”，项目主任是Kristen Keefe博士）;和（iii）先前暴露于由逐渐增加的METH剂量引起的暂时耐受的大鼠（项目#3-“耐受性相关的可逆不应性”，项目负责人是Diana Wilkins博士）。预计阐明这3种难治模型的机制将为以下问题提供信息：（一）青少年药物滥用的脆弱性;（二）青少年发育期间使用甲基苯丙胺的影响;以及（三）成年期间甲基苯丙胺相关神经毒性的持续影响。 项目特点

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