Long-term consequences of methamphetamine toxicity

甲基苯丙胺中毒的长期后果

• 批准号: 7530201
• 负责人: KRISTEN A KEEFE
• 金额: $ 34.44万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7530201
• 关键词: Animal Model; Animals; Antisense Oligonucleotides; Basal Ganglia; Behavior; Behavioral; Brain; Cognitive; Condition; Corpus striatum structure; Cues; Data; Development; Dopamine; Efferent Neurons; Efferent Pathways; Electric Stimulation; Gene Expression; Goals; Hippocampus (Brain); Human; Immediate-Early Genes; Impairment; Infusion procedures; Laboratories; Learning; Long-Term Effects; Measures; Mediating; Memory; Messenger RNA; Methamphetamine; Midbrain structure; Molecular; Motor; Nature; Nervous System Physiology; Neuraxis; Neuronal Plasticity; Neurons; Outcome; Parkinson Disease; Patients; Phase; Population; Property; Public Health; Rattus; Regulation; Relative (related person); Response to stimulus physiology; Reversal Learning; Role; Scanning; Serotonin; Signal Transduction; Site; Synapses; System; Toxic effect; Transcriptional Activation; base; dopamine system; extracellular; improved; indexing; mRNA Expression; median forebrain bundle; memory process; monoamine; morris water maze; nerve supply; neurotoxicity; neurotransmission; pre-clinical; putamen; research study; size; stimulant abuse; transmission process; uptake

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.

描述（由申请人提供）：滥用甲基苯丙胺（METH）的长期后果包括大脑中单胺系统的持续、部分丧失，特别是纹状体的多巴胺神经支配。尽管多巴胺消耗较小时，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着影响。纹状体多巴胺摄取位点减少的戒毒者和帕金森病早期患者都表现出认知任务缺陷。对部分单胺耗竭的动物的研究表明，依赖于纹状体、海马和皮质功能的学习和记忆功能存在缺陷，我们实验室的最新数据表明，这种缺陷可能与效应子立即早期基因弧的激活受损有关。部分多巴胺耗竭也与模仿阶段性多巴胺信号传导的电刺激引起的多巴胺浓度降低有关。最后，部分单胺消耗与纹状体黑质（直接通路）传出神经元功能测量的变化有关。总而言之，这些数据表明，纹状体的部分多巴胺耗竭会选择性地改变纹状体黑质神经元功能，从而通过损害阶段性多巴胺神经传递来改变基底神经节依赖性学习和记忆功能。该假设将通过以下方式进行检验：1）进一步表征冰毒引起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）确定冰毒引起的神经毒性是否与多巴胺瞬变的降解有关，以及激活阶段性多巴胺传递是否会选择性增强纹状体黑质神经元功能； 3) 检查冰毒诱导的神经毒性对弧诱导和细胞质分布以及纹状体弧参与学习和记忆的影响。完成这些实验将有助于更好地了解冰毒引起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。这种理解对于制定有针对性的策略来治疗性管理此类兴奋剂滥用的长期影响至关重要。公共卫生相关性 现在已经确定，甲基苯丙胺 (METH) 滥用会导致人类以及其他物种尾壳核的多巴胺神经支配长期减少。该项目的目标是进一步确定冰毒引起的神经毒性对基底神经节功能和基底神经节介导的学习和记忆过程的影响，并评估阶段性多巴胺神经传递的变化是否是冰毒对基底神经节功能和行为的长期影响的基础。