NEUROCHEMICAL PATHOLOGY OF HUMAN COCAINE ABUSE

尽管发表了大量的实验室动物研究， 有证据表明可卡因对特定的中枢神经系统有影响 神经递质系统，有显着鲜为人知的是， 这种精神兴奋剂对人脑的长期影响。在这 建议我们寻求审查长期滥用可卡因的影响， 通过评估大约50个大脑中的神经化学变化， 从已证实的可卡因滥用者死后脑组织中提取的区域 (with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。通过可卡因的作用 单胺转运蛋白，临床前文献已明确暗示 多巴胺（DA）、5-羟色胺（5 MT）和去甲肾上腺素（NE）神经元 在调解可卡因的行动;也有相当多的证据表明， 涉及两个神经肽神经元系统（促肾上腺皮质激素释放 因子[CRF]和神经降压素[NT]）的作用。 将通过测量来评估单胺转运蛋白的改变 放射性配体结合，转运蛋白浓度，通过使用 新开发的针对转运蛋白的特异性抗体，以及mRNA 运输者的表达。通用报告格式和NT系统的改动将 通过测量神经肽、神经肽mRNA 表达，神经肽受体结合，神经肽受体mRNA 表达，并且在CRF系统的情况下，CRF结合蛋白和 CRF信号转导。这些研究将提供关于 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.