Long-term consequences of methamphetamine toxicity

甲基苯丙胺中毒的长期后果

• 批准号: 8267683
• 负责人: KRISTEN A KEEFE
• 金额: $ 32.52万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267683
• 关键词: Animal Model; Animals; Antisense Oligonucleotides; Basal Ganglia; Behavior; Behavioral; Brain; Cognitive; Corpus striatum structure; Cues; Data; Development; Dopamine; Efferent Neurons; Electric Stimulation; Gene Expression; Goals; Health; 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; Pathway interactions; Patients; Phase; Population; Property; 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; methamphetamine abuse; monoamine; morris water maze; nerve supply; neurotoxicity; neurotransmission; pre-clinical; putamen; research study; 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(申请人提供)：甲基苯丙胺(冰毒)滥用的长期后果包括大脑中单胺系统的持续性、部分丧失，特别是纹状体的多巴胺神经支配。尽管在较小规模的多巴胺缺乏时，功能明显相对节制，但有几条证据表明，这种部分多巴胺丧失对中枢神经系统功能有重大影响。无论是有记录的纹状体多巴胺摄取部位减少的禁欲冰毒滥用者，还是帕金森病病程早期的患者，都显示出认知任务的缺陷。对部分单胺缺乏的动物的研究表明，学习和记忆功能的缺陷依赖于纹状体、海马体和皮质功能，最近来自我们实验室的数据表明，这种缺陷可能与效应器即刻早期基因弧的激活受损有关。部分多巴胺缺乏也与模拟时相多巴胺信号的电刺激引起的多巴胺浓度降低有关。最后，部分单胺缺乏与纹状体(直接通路)传出神经元功能指标的改变有关。综上所述，这些数据表明，纹状体多巴胺的部分缺失通过损害相的多巴胺神经传递，选择性地改变纹状体黑质神经元的功能，从而改变基底节依赖的学习和记忆功能。这一假说将通过1)进一步表征冰毒诱导的神经毒性对基底节介导的学习和记忆过程的影响；2)确定冰毒诱导的神经毒性是否与多巴胺瞬时降解有关，以及激活相多巴胺传递是否将选择性地增强纹状体黑质神经元的功能；以及3)检测冰毒诱导的神经毒性对弧线诱导和细胞质分布以及纹状体弧线参与学习和记忆的影响。这些实验的完成将有助于更好地了解冰毒对中枢多巴胺系统的神经毒性对基底神经节功能的分子、细胞和行为影响。这种了解对于制定有针对性的战略，从治疗上管理这类兴奋剂滥用的长期影响至关重要。公共卫生相关性现已证实，滥用甲基苯丙胺(冰毒)会导致人类以及其他物种尾壳核多巴胺神经支配的长期减少。本项目的目的是进一步确定冰毒诱导的神经毒性对基底节功能和基底节介导的学习记忆过程的影响，并评估多巴胺时相神经传递的变化是否是冰毒对基底节功能和行为的长期影响的基础。

项目成果

Impaired formation of stimulus-response, but not action-outcome, associations in rats with methamphetamine-induced neurotoxicity.

大鼠中刺激反应形成受损，但行动结果与甲基苯丙胺诱导的神经毒性无关。

• DOI: 10.1038/npp.2011.131
• 发表时间: 2011
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Son,Jong-Hyun;Latimer,Christine;Keefe,KristenA
• 通讯作者: Keefe,KristenA

Changes in neural circuitry regulating response-reversal learning and Arc-mediated consolidation of learning in rats with methamphetamine-induced partial monoamine loss.

甲基苯丙胺诱导的部分单胺丧失的大鼠中调节反应逆转学习和 Arc 介导的学习巩固的神经回路的变化。

• DOI: 10.1038/npp.2013.296
• 发表时间: 2014
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Pastuzyn,ElissaD;Keefe,KristenA
• 通讯作者: Keefe,KristenA

Methamphetamine-induced neurotoxicity disrupts pharmacologically evoked dopamine transients in the dorsomedial and dorsolateral striatum.

• DOI: 10.1007/s12640-014-9459-y
• 发表时间: 2014-08
• 期刊: Neurotoxicity research
• 影响因子: 3.7
• 作者: Robinson JD;Howard CD;Pastuzyn ED;Byers DL;Keefe KA;Garris PA
• 通讯作者: Garris PA

Perseverative behavior in rats with methamphetamine-induced neurotoxicity.

甲基苯丙胺诱导的神经毒性大鼠的持续行为。

• DOI: 10.1016/j.neuropharm.2012.09.021
• 发表时间: 2013
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Son,Jong-Hyun;Kuhn,James;Keefe,KristenA
• 通讯作者: Keefe,KristenA

Phasic-like stimulation of the medial forebrain bundle augments striatal gene expression despite methamphetamine-induced partial dopamine denervation.

尽管甲基苯丙胺诱导部分多巴胺去神经，但内侧前脑束的阶段性刺激增强了纹状体基因表达。

• DOI: 10.1111/jnc.12234
• 发表时间: 2013
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Howard,ChristopherD;Pastuzyn,ElissaD;Barker-Haliski,MelissaL;Garris,PaulA;Keefe,KristenA
• 通讯作者: Keefe,KristenA