CNS Mechanisms in Cocaine Related Sudden Death

可卡因相关猝死的中枢神经系统机制

• 批准号: 7102679
• 负责人: DEBORAH C. MASH
• 金额: $ 26.63万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-10 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102679
• 关键词: alpha synuclein; amygdala; autonomic nervous system; autoradiography; brain; central nervous system; clinical research; cocaine; death; delirium; dopamine; dopamine transporter; gene expression; human tissue; membrane transport proteins; messenger RNA; neuroanatomy; neurochemistry; neurotransmitter transport; norepinephrine; opioid receptor; postmortem; serotonin; tissue resource /registry; toxicology

DESCRIPTION (provided by applicant): Cocaine is a reinforcing drug with high abuse liability and substantial morbidity and mortality. Cocaine's potent actions on dopamine (DA), serotonin (5-HT) and norepinephrine (NE) transport are well known. However, the relationship between the long-term effects of chronic cocaine abuse and the regional neuroadaptive changes in human brain is less certain. Because the transit of cocaine from the Caribbean corridor to the United States frequently occurs through South Florida, Metropolitan Miami-Dade County has continued to have a high incidence of cocaine-related deaths. In collaboration with the Miami-Dade County Medical Examiner Department, we have developed a bank of postmortem brain specimens from cocaine users. Based on a retrospective case control analysis of the toxicology reports, scene descriptions, supplemental background information, interviews with next-of-kin, and autopsy findings, we assign cases into three groups: cocaine-related sudden death, excited cocaine delirium, and drug-free control subjects. The proposed studies are designed to identify neuroadaptive and neurodegenerative changes in biogenic amine pathways in the postmortem human brain. Neuroadaptation and neurodegeneration in DA, 5-HT and NE systems are central to the vulnerability, progression and long-term consequences of addictive behavior. DAergic signaling underlies the reinforcing properties of cocaine, while serotonergic dysfunction may be associated with behavioral disinhibition and negative mood states. Recent studies of the noradrenergic system suggest that a dysregulation of NE transport by cocaine may contribute to cerebrogenic cardiovascular and autonomic disturbances that lead to sudden death. Specifically, we plan to test the following hypotheses: 1.) DA transporter upregulation occurs in parallel with an increase in the expression of alpha-synuclein protein in DA and NE neurons. 2.) Asymmetric changes in NE transporter expression occurs in higher brain autonomic centers (insula and amygdaloid subnuclei) in cocaine-related sudden death as compared to age-matched drug-free control subjects. This neuroadaptive change in NET will be a specific marker of cocaine toxicity. 3.) Regulatory changes in biogenic amine transporters and kappa opioid receptor numbers will show lateral asymmetry in the amygdala and anterior insular cortex. 4.) Changes in particular biogenic amine transporters and gene transcripts are specific to the pathology of cocaine excited delirium. The power of the proposed study derives from an integration of molecular and anatomical approaches in examining postmortem human brain from chronic cocaine users. Together, these studies will provide a molecular and circuit-based accounting of the abnormalities in biogenic amine systems in cocaine toxicity.

描述（由申请人提供）：可卡因是一种强化药物，具有很高的滥用可能性和较高的发病率和死亡率。可卡因对多巴胺 (DA)、血清素 (5-HT) 和去甲肾上腺素 (NE) 运输的强大作用是众所周知的。然而，长期滥用可卡因的长期影响与人脑区域神经适应性变化之间的关系尚不确定。由于可卡因经常通过南佛罗里达州从加勒比走廊转运到美国，迈阿密大都会-戴德县与可卡因相关的死亡发生率仍然很高。我们与迈阿密戴德县法医部门合作，开发了可卡因吸食者死后大脑样本库。根据毒理学报告、场景描述、补充背景信息、近亲访谈和尸检结果的回顾性病例对照分析，我们将病例分为三组：可卡因相关猝死、兴奋性可卡因谵妄和药物性谵妄。 -自由对照受试者。拟议的研究旨在确定死后人脑中生物胺途径的神经适应性和神经退行性变化。 DA、5-HT 和 NE 系统中的神经适应和神经变性对于成瘾行为的脆弱性、进展和长期后果至关重要。 DAergic 信号传导是可卡因增强特性的基础，而血清素能功能障碍可能与行为去抑制和负面情绪状态有关。最近对去甲肾上腺素能系统的研究表明，可卡因对去甲肾上腺素转运的失调可能会导致脑源性心血管和自主神经紊乱，从而导致猝死。具体来说，我们计划测试以下假设：1.) DA 转运蛋白上调与 DA 和 NE 神经元中 α-突触核蛋白表达的增加同时发生。 2.) 与年龄匹配的未吸毒对照受试者相比，可卡因相关猝死的高级大脑自主中心（岛叶和杏仁核亚核）的 NE 转运蛋白表达发生不对称变化。 NET 的这种神经适应性变化将是可卡因毒性的特定标志。 3.) 生物胺转运蛋白和 kappa 阿片受体数量的调节变化将显示杏仁核和前岛叶皮质的横向不对称。 4.) 特定生物胺转运蛋白和基因转录物的变化是可卡因兴奋性谵妄病理学特有的。这项研究的力量来源于分子和解剖学方法的整合，用于检查长期可卡因使用者死后的人脑。总之，这些研究将为可卡因毒性中生物胺系统的异常提供基于分子和电路的解释。