Long-term consequences of methamphetamine toxicity

描述（由申请人提供）：甲基苯丙胺（冰毒）滥用的长期后果包括大脑单胺系统的持续、部分丧失，特别是纹状体多巴胺神经支配。尽管在较小规模的多巴胺耗竭中，功能明显相对保留，但一些证据表明，这种部分多巴胺损失对中枢神经系统功能有显著影响。纹状体多巴胺摄取部位减少的戒断性冰毒滥用者和帕金森病早期患者在认知任务上都表现出缺陷。对部分单胺消耗的动物的研究表明，依赖纹状体、海马和皮质功能的学习和记忆功能缺陷，我们实验室最近的数据表明，这种缺陷可能与效应立即早期基因弧的激活受损有关。部分多巴胺消耗也与电刺激引起的多巴胺浓度下降有关，电刺激模拟了阶段性多巴胺信号。最后，部分单胺消耗与纹状体纹状体（直接通路）传出神经元功能测量的变化有关。综上所述，这些数据表明纹状体的部分多巴胺消耗选择性地改变了纹状体神经元的功能，从而通过损害阶段性多巴胺神经传递，改变了依赖基底神经节的学习和记忆功能。这一假设将通过以下方式得到验证：1)进一步表征甲基苯丙胺诱导的神经毒性对基底神经节介导的学习和记忆过程的影响；2)确定甲基苯丙胺诱导的神经毒性是否与多巴胺瞬态降解有关，激活多巴胺相传递是否会选择性地增强纹状体神经元的功能；3)研究甲基冰毒诱导的神经毒性对弧的诱导和细胞质分布以及纹状体弧参与学习和记忆的影响。这些实验的完成将提高对甲基安非他明诱导的中枢多巴胺系统神经毒性对基底神经节功能的分子、细胞和行为影响的理解。这种理解对于制定有针对性的策略，以治疗性地管理这种兴奋剂滥用的长期影响至关重要。现在已经确定，甲基苯丙胺（冰毒）滥用导致人类以及其他物种尾状壳核多巴胺神经支配的长期减少。该项目的目的是进一步确定甲基安非他明诱导的神经毒性对基底节区功能和基底节区介导的学习和记忆过程的影响，并评估甲基安非他明对基底节区功能和行为的长期影响是否基于阶段性多巴胺神经传递的变化。

DESCRIPTION (provided by applicant): The long-term consequences of methamphetamine (METH) abuse include a persistent, partial loss of monoamine systems in the brain, particularly the dopamine innervation of the striatum. Despite the apparent relative sparing of function at smaller sizes of dopamine depletion, several lines of evidence suggest that there is a significant impact of such partial dopamine loss on central nervous system function. Both abstinent METH abusers with documented decreases in dopamine uptake sites in striatum and patients early in the course of Parkinson's disease show deficits on cognitive tasks. Studies in animals with partial monoamine depletions have revealed deficits in learning and memory functions dependent on striatal, hippocampal, and cortical function, and recent data from our laboratory suggest that such deficits may be associated with impaired activation of the effector immediate early gene arc. Partial dopamine depletions also are associated with decreased dopamine concentrations evoked by electrical stimulation mimicking phasic dopamine signaling. Finally, partial monoamine depletions are associated with changes in measures of the function of striatonigral (direct pathway) efferent neurons of striatum. Taken together, these data suggest that partial dopamine depletions of striatum selectively alter striatonigral neuron function and, consequently, basal ganglia- dependent learning and memory function by impairing phasic dopamine neurotransmission. This hypothesis will be examined by 1) further characterizing the impact of METH-induced neurotoxicity on basal ganglia-mediated learning and memory processes; 2) determining whether METH-induced neurotoxicity is associated with degradation of dopamine transients and whether activating phasic dopamine transmission will selectively enhance striatonigral neuron function; and 3) examining the impact of METH-induced neurotoxicity on arc induction and cytoplasmic distribution as well as on the involvement of striatal Arc in learning and memory. Completion of these experiments will provide improved understanding of the molecular, cellular, and behavioral impact of METH-induced neurotoxicity to central dopamine systems on basal ganglia function. Such understanding will be critical to allow for the development of targeted strategies to therapeutically manage the long-term effects of such stimulant abuse. PUBLIC HEALTH RELEVANCE It is now established that methamphetamine (METH) abuse leads to long-lasting decreases in the dopamine innervation of the caudate-putamen in humans, as well as other species. The goal of this project is to further determine the impact of METH- induced neurotoxicity on basal ganglia function and basal ganglia-mediated learning and memory processes and to assess whether changes in phasic dopamine neurotransmission underlie the long-term effects of METH on basal ganglia function and behavior.