BRAIN AND BEHAVIOR ALTERATIONS AFTER METHAMPHETAMINE

描述：(申请人摘要) 尽管滥用人类甲基苯丙胺(MeAmp)的功能后果 已经被广泛地记录下来，潜在的神经生物学机制 对于这些行为，仍然没有具体说明。更进一步，神经化学的发现 从动物研究中还没有产生一个连贯的数据库来进行建模 人类滥用MeAmp的行为影响。拟议的研究将使用 正电子发射断层扫描(PET)、行为学和 用免疫组织化学方法模拟人MeAmp暴露组分 体色鲜艳的猴子。急性、低剂量MeAmp方案(2×2 mg/kg)将是 用来产生纹状体多巴胺系统类似神经毒性的图案 与最近在人死后组织中观察到的慢性MeAmp 施虐者。结果将表明，在非人类灵长类动物中，两者的 MeAmp诱导的纹状体多巴胺缺乏和行为后遗症 在8个月内可逆；此外， 神经化学和行为恢复将在 压力源-环境(不可预测和不稳定的社会关系)。在… 注射MeAmp 1个月后，突触前纹状体减少 多巴胺受体密度将用PET和[11C]WIN35,428，a 多巴胺转运蛋白的标志物。在进行正电子发射计算机断层扫描的同时， 运动、社会和认知行为将在自然主义的 布景。以1个月赢利赤字为纳入标准，MeAmp 然后受试者将被分成两组：一组将被保留 通常在它的社会群体中，另一个受到一系列破坏性的 以及不稳定的社会关系。通过这种方式，我们将确定 环境应激源及其诱发行为的意义 MeAmp诱导的生化和组织损伤恢复的易损性因素 行为缺陷。脑内多巴胺能的尸检分析 (黑质纹状体、中脑边缘和中皮质)和胶质细胞指数将定义 甲氨蝶呤诱导的神经毒理学改变(1个月)和 可逆性程度(8个月)。这些研究将 MeAmp在非人类体内的长期神经生物学毒理学研究 并将展示Win-PET在评估 为治疗神经毒性而设计的药物疗法的疗效 MeAmp暴露。

DESCRIPTION: (Applicant's Abstract) Although the functional consequences of human methamphetamine (MeAmp) abuse have been extensively documented, the underlying neurobiological mechanisms for those behaviors remain unspecified. Further, neurochemical findings from animal studies have not yielded a cohesive database from which to model the behavioral effects of human MeAmp abuse. The proposed studies will use a unique combination of positron emission tomography (PET), ethological, and immunohistochemical methods to model components of human MeAmp exposure in vervet monkeys. An acute, low dose MeAmp protocol (2 X 2 mg/kg) will be used to produce a pattern of striatal dopamine system neurotoxicity similar to that recently observed in postmortem tissue of human, chronic MeAmp abusers. The results will show that in non-human primates, both the MeAmp-induced striatal dopamine deficits and behavioral sequelae are reversible over an 8 month period; further, that the extent of the neurochemical and behavioral recovery will be reduced in a stressor-environment (unpredictable and unstable social relationships). At 1 month following MeAmp administration, decreases in presynaptic striatal dopamine receptor density will be measured with PET and [11C]WIN35,428, a marker for dopamine transporters. Concurrent with PET, alterations in motor, social and cognitive behaviors will be assessed within a naturalistic setting. With the 1 month WIN deficits as inclusion criteria, the MeAmp subjects will then be divided into two cohorts: one will be maintained normally in its social group, the other subjected to a series of disruptive and unstable social relationships. In this manner, we will determine the significance of an environmental stressor and its evoked behaviors as vulnerability factors for recovery of MeAmp-induced biochemical and behavioral deficits. Postmortem brain analyses of dopaminergic (nigrostriatal, mesolimbic and mesocortical) and glial indices will define the neurotoxicological profile of MeAmp-induced alterations (1 month) and the extent of their reversibility (8 months). These studies will characterize the long-term, neurobiological toxicology of MeAmp in non-human primates and will demonstrate the potential of WIN-PET for evaluating the efficacy of pharmacological therapies designed for treatment of neurotoxic MeAmp exposure.