BRAIN & BEHAVIORAL ALTERATIONS AFTER METHAMPHETAMINE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。人类滥用甲基苯丙胺（冰毒）的行为后果已被广泛记载。然而，这些行为的潜在神经生物学机制仍未明确。对这些过程进行更精确和彻底的检查仍然需要使用适当的动物模型来处理人类广泛的滥用模式。在拟议的研究中，我们将通过对生物、心理和环境决定因素的综合评估来模拟人类在非人类灵长类动物中慢性甲基安非他明暴露的各个方面。将对生活在自然组成的社会群体中的长尾猴（Cercopithecus aethiops sabaeus）实施6个月的甲基苯丙胺剂量逐步增加方案，以反映人类甲基苯丙胺滥用模式。在整个研究过程中，PET将在体内测定突触前纹状体多巴胺（DA）转运体结合减少的情况，以建立其敏感性，作为体内对甲基安非他明的行为反应性指标。冲动、攻击性和社会关系的行为改变将在冰毒暴露期间进行评估，然后在冰毒戒断期后持续6个月，以评估潜在的恢复情况。认知改变将通过一系列神经心理学任务进行评估。人类对冰毒行为反应的个体差异将通过测量冰毒前脑脊液单胺代谢物水平（HVA, 5-HIAA， MHPG）及其在冰毒后变化的程度来评估冰毒受试者。通过死后测量黑质细胞损失、突触前转运体和突触后受体密度（DA 1、DA2、5- ht1a、5-HT2A），评估甲基安非他明在皮层、黑质纹状体和边缘区域的多巴胺和血清素通路中表达的神经毒性。研究结果将显示，在群居的成年非人灵长类动物中，局部大脑系统对甲基安非他明暴露的脆弱性与特定行为和认知评估相结合。这一模式将代表一种有效的灵长类动物模型，以评估用于治疗与人类滥用冰毒相关的神经和行为缺陷的药物疗法的疗效

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 abus