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Brain and Behavioral Alterations After Methamphetamine

甲基苯丙胺后大脑和行为的改变

基本信息

批准号：
6908044
负责人：
William P. Melega
金额：
$ 1.34万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-30 至 2005-03-31
项目状态：
已结题

项目摘要

DESCRIPTION: Behavioral consequences of human methamphetamine (METH) abuse have been extensively documented. However, underlying neurobiological mechanisms for those behaviors remain unspecified. A more precise and thorough examination of those processes still requires the use of appropriate animal models that address the broad range of abuse patterns in humans. For the proposed studies, we will model aspects of human chronic METH exposure in nonhuman primates with an integrated evaluation of biological, psychological, and environmental determinants. A 6 month escalating METH dose protocol that reflects human METH abuse patterns will be administered to vervet monkeys (Cercopithecus aethiops sabaeus) housed in naturally composed social groups. Presynaptic striatal dopamine (DA) transporter binding decreases will be determined in vivo throughout the study with PET to establish its sensitivity as an in vivo index of behavioral reactivity to METH. Behavioral alterations of impulsivity, aggression, and social relationships will be evaluated throughout the METH exposure and then continued for 6 months post-METH abstinence period to assess potential recovery. Cognitive alterations will be assessed by a battery of neuropsychological tasks. Individual differences in behavioral reactivity to METH, which are often seen in humans, will be evaluated in our METH subjects by measurement of pre-METH CSF monoamine metabolite levels (HVA, 5-HIAA, MHPG) and the extent of their changes, post-METH. Neurotoxicity of METH as expressed in dopamine and serotonin pathways within cortical, nigrostriatal and limbic regions will be evaluated by post-mortem measures of substantia nigra cell loss, pre-synaptic transporter and post-synaptic receptor densities (DA 1, DA2, 5-HT 1 A, 5-HT2A). The results will show in socially-housed adult nonhuman primates, the vulnerability of regional brain systems to METH exposure in conjunction with specific behavioral and cognitive assessments. This paradigm will represent a validated primate model to evaluate the efficacy of pharmacotherapies designed for treatment of neurological and behavioral deficits associated with human METH abuse.

描述：人类甲基苯丙胺（METH）滥用的行为后果被广泛记录。然而，潜在的神经生物学机制，这些行为仍未明确。更精确和彻底的检查这些过程仍然需要使用适当的动物模型，解决人类广泛的虐待模式。对于拟议的研究，我们将在非人类灵长类动物中模拟人类慢性METH暴露的各个方面，生物、心理和环境的综合评估决定因素一个6个月的逐步增加的甲基剂量协议，反映了人类的甲基将对长尾猴（Cercopithecus aethiops）实施滥用模式 sabaeus）居住在自然组成的社会群体中。突触前纹状体将在体内测定多巴胺（DA）转运蛋白结合减少在整个研究过程中，使用PET确定其作为体内指标的灵敏度对甲安菲他明的行为反应冲动的行为改变，攻击性和社会关系将在整个方法中进行评估暴露，然后在METH戒断期后持续6个月，以评估潜在的恢复。认知改变将通过一组神经心理学任务行为反应的个体差异 METH，这是经常在人类中看到，将在我们的METH科目进行评估，测量METH前CSF单胺代谢物水平（HVA、5-HIAA、MHPG）和他们的变化程度，后甲基。METH的神经毒性，以皮质、黑质纹状体和边缘系统内的多巴胺和5-羟色胺通路将通过黑质细胞的死后测量来评价区域损失、突触前转运蛋白和突触后受体密度（DA 1，DA 2， 5-HT 1A、5-HT 2A）。结果将显示在社会圈养的成年非人类灵长类动物，区域大脑系统对METH暴露的脆弱性，结合具体的行为和认知评估。这种范式将代表经验证的灵长类动物模型，以评价用于治疗神经和行为疾病的药物疗法与人类滥用甲基苯丙胺有关的缺陷。