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，具有高虐待责任，发病率和死亡率。可卡因对多巴胺（DA），5-羟色胺（5-HT）和去甲肾上腺素（NE）的运输的有效作用是众所周知的。然而，慢性可卡因滥用的长期影响与人脑的区域神经适应性变化之间的关系不太确定。由于可卡因从加勒比海走廊过渡到美国，经常通过南佛罗里达州发生，因此迈阿密大都会县大都会县继续发生与可卡因相关的死亡发生率很高。与迈阿密戴德县医学检查员部门合作，我们开发了可卡因用户的验尸脑标本。基于对毒理学报告，场景描述，补充背景信息，与临近感染的访谈和尸检结果的回顾性病例控制分析，我们将病例分为三组：与可卡因有关的猝死，激发的可卡因妄想和无药物对照对象。拟议的研究旨在鉴定验尸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是成瘾行为的脆弱性，进展和长期后果的核心。 DAergic信号传导是可卡因的增强特性的基础，而血清素能功能障碍可能与行为抑制和负情绪状态有关。对去甲肾上腺素能系统的最新研究表明，可卡因对NE转运的失调可能导致脑血管心血管和自主性障碍导致猝死。具体而言，我们计划检验以下假设：1。）DA转运蛋白上调与DA和NE神经元中α-突触核蛋白蛋白的表达同时出现。 2.）与不匹配的无药物对照组相比，与可卡因相关相关的猝死中，NE转运蛋白表达的不对称变化发生在较高的脑自主神经中心（岛和杏仁核亚核中）。净的这种神经适应性变化将是可卡因毒性的特定标记。 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状皮质中的横向不对称性。 4.）特定生物胺转运蛋白和基因转录本的变化是可卡因激发del妄的病理学的。拟议研究的力量源于分子和解剖方法的整合，以检查慢性可卡因使用者的死后人脑。总之，这些研究将提供可卡因毒性生物胺系统异常的分子和电路的分子占。