Brain and Behavioral Alterations After Methamphetamine

描述：人类滥用甲基苯丙胺的行为后果有 被广泛记录在案。然而，潜在的神经生物学机制 这些行为仍然没有具体说明。更精确、更彻底的检查 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冰毒暴露的各个方面 对生物、心理和环境的综合评价 决定因素。反映人类冰毒的6个月递增冰毒剂量方案 虐待模式将用于鞭毛猴(Cercopithecus Atheiops) 住在自然组成的社会团体中。突触前纹状体 多巴胺(DA)转运体结合减少将在体内确定 通过对PET的研究，建立其敏感性作为活体指标 对冰毒的行为反应。冲动的行为变化， 攻击性和社会关系将在整个冰毒过程中进行评估 然后在冰毒戒断后持续6个月的时间进行评估 潜在的恢复。认知改变将通过一组 神经心理学任务。行为反应性的个体差异 在人类中常见的冰毒，将通过以下方式在我们的冰毒受试者中进行评估 冰毒前脑脊液单胺代谢物(HVA、5-HIAA、MHPG)和 冰毒后，他们变化的程度。冰毒的神经毒性，表达在 皮质、黑质纹状体和边缘的多巴胺和5-羟色胺通路 区域将通过黑质细胞的死后测量进行评估 突触前转运体和突触后受体密度(DA1，DA2， 5-羟色胺1A、5-羟色胺2A)。这一结果将在社交场所居住的非人类成年人身上显示出来。 灵长类动物，区域大脑系统对冰毒暴露的脆弱性 结合具体的行为和认知评估。这一范式 将代表一个经过验证的灵长类动物模型来评估 治疗神经和行为疾病的药物疗法 与人类滥用冰毒有关的缺陷。

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.