NEUROCHEMICAL PATHOLOGY OF HUMAN COCAINE ABUSE

尽管有大量已发表的关于实验室动物的研究 记录了可卡因对特定中枢神经系统的影响 神经递质系统，人们对此知之甚少 这种精神刺激剂对人类大脑的慢性影响。在这 我们寻求审查长期滥用可卡因的影响的提案 通过评估约50个大脑的神经化学变化来评估人类 从确认的可卡因滥用者死后脑组织中提取的区域 (用分段毛发分析记录可卡因的时间模式 使用)和年龄和性别匹配的对照。通过可卡因对 单胺转运体，临床前文献清楚地表明 多巴胺、5-羟色胺和去甲肾上腺素能神经元 在调解可卡因的行为方面，也有相当多的证据 涉及两个神经肽神经系统(促肾上腺皮质激素释放 因子[CRF]和神经降压素[NT])在这种滥用药物的作用中。 单胺转运体的改变将通过测量进行评估 放射性配基结合，转运蛋白浓度通过使用 新开发的针对转运蛋白和mRNA的特异性抗体 转运蛋白的表达。CRF和NT系统的更改将是 通过测定神经肽、神经肽信使核糖核酸 表达、神经肽受体结合、神经肽受体mRNA 表达，在CRF系统的情况下，CRF结合蛋白和 CRF信号转导。这些研究将提供有关 可卡因滥用对人体特定神经递质系统的影响 中枢神经系统。

In spite of a plethora of published studies in laboratory animals that have documented effects of cocaine on specific central nervous system neurotransmitter systems, there is remarkably little known about the chronic effects of this psychostimulant on the human brain. In this proposal we seek to scrutinize the effects of chronic cocaine abuse in humans by assessment of neurochemical alteration in approximately 50 brain regions derived from post-mortem brain tissue of confirmed cocaine abusers (with segmental hair analysis to document the temporal pattern of cocaine use) and age- and sex-matched controls. Through cocaine's actions on monoamine transporters, the preclinical literature has clearly implicated dopamine (DA), serotonin (5MT) and norepinephrine (NE)-containing neurons in mediating the actions of cocaine; there is also considerable evidence implicating two neuropeptide neuronal systems (corticotropin-releasing factor [CRF] and neurotensin [NT]) in the actions of this drug of abuse. Alterations in the monoamine transporters will be assessed by measurement of: radioligand binding, transporter protein concentration by the use of newly developed specific antibodies to the transporters, and mRNA expression of the transporters. Alterations in CRF and NT systems will be assessed by measurement of the neuropeptides, neuropeptide mRNA expression, neuropeptide receptor binding, neuropeptide receptor mRNA expression, and in the case of the CRF system, the CRF-binding protein and CRF signal transduction. These studies will provide novel data on the effects of cocaine abuse on specific neurotransmitter systems in the human central nervous system.