BRAIN AND BEHAVIOR ALTERATIONS AFTER METHAMPHETAMINE

服用甲基苯丙胺后大脑和行为的改变

• 批准号: 2749184
• 负责人: William P. Melega
• 金额: $ 28.06万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2749184
• 关键词: Cercopithecidae; behavioral /social science research tag; dopamine antagonists; dopamine receptor; dopamine transporter; ethology; histopathology; immunocytochemistry; methamphetamine; neurotoxicology; positron emission tomography; postmortem; psychomotor function; psychopharmacology; social behavior; species difference; tropanes

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.

描述：（申请人摘要） 虽然滥用人用甲基安非他明的功能性后果 已经被广泛地记录了，潜在的神经生物学机制 对这些行为的影响还未明确。 此外，神经化学发现 从动物研究中还没有产生一个有凝聚力的数据库， 人类滥用冰毒的行为影响 拟议的研究将使用 正电子发射断层扫描（PET），行为学， 免疫组织化学方法来模拟人类暴露于 长尾猴 将进行急性低剂量甲孕酮方案（2 X 2 mg/kg）， 用于产生类似于纹状体多巴胺系统神经毒性的模式 最近在人类死后组织中观察到的慢性代谢综合征， 施虐者 结果将表明，在非人类灵长类动物中， MeAmp诱导的纹状体多巴胺缺陷和行为后遗症是 在8个月的时间内可逆;此外， 神经化学和行为恢复将减少在一个 压力源-环境（不可预测和不稳定的社会关系）。 在 美托洛尔给药后1个月，突触前纹状体 多巴胺受体密度将用PET和[11 C] WIN 35，428测量，a 多巴胺转运蛋白的标志物。 与PET同时， 运动，社会和认知行为将在一个自然的评估 设置. 以1个月WIN缺陷作为入选标准， 然后将受试者分为两个队列：一个将维持 通常在其社会群体中，另一个受到一系列破坏性的影响， 不稳定的社会关系。 这样，我们将确定 环境应激源及其诱发行为作为 恢复MeAmp诱导的生化和 行为缺陷 多巴胺能神经递质的死后脑分析 （黑质纹状体、中边缘和中皮质）和胶质细胞指数将定义 MeAmp诱导的改变的神经毒理学特征（1个月）， 其可逆性程度（8个月）。 这些研究将 描述美托洛尔在非人类中的长期神经生物学毒理学特征 灵长类动物，并将证明WIN-PET用于评估 设计用于治疗神经毒性的药物治疗的有效性 暴露在毒气中。