CHRONIC COCAINE AND HUMAN BRAIN DOPAMINE

尽管人们花了大量的精力来了解可卡因的大脑基质， 通过实验动物的生物化学研究， 可卡因成瘾的原因仍然不明。我们建议， 神经化学研究也应在人脑中进行 可卡因吸食者 在对10名可卡因使用者进行的尸检大脑研究中， 观察到一种特定的神经递质多巴胺的浓度降低 (DA)，在脑桥核--一个被认为与 调节可卡因的急性和长期影响。具体 我们建议调查的目的是检查可靠性， DA的可逆性、原因、药物和神经化学特异性 还原我们要检验的主要假设是， 可卡因和其他药物滥用将与减少 多巴胺、多巴胺生物合成酶和多巴胺水平 运输机，最终被逆转。这一假设将得到检验 通过生化检查，通过HPLC，Western Blot， 放射自显影方法，DA水平，DA生物合成酶 酪氨酸羟化酶和多巴脱羧酶，以及多巴胺转运蛋白， 尸检的大脑中至少有10个可卡因，5个鸦片，5个 甲基苯丙胺，和五个酒精使用者在每三年， 我们的调查这项研究的一个特点是我们能够 从美国法医那里获得吸毒者的大脑尸检 特征在于药物类型、持续时间和模式。我们预计 我们的调查结果将提供一个强大的测试， “可卡因成瘾的DA耗竭假说”，同时， 解决可卡因对人脑DA毒性的重要医学问题 神经元最终，这些信息将有助于澄清 丘脑腹侧核DA系统对行为神经元的作用 使用可卡因对人类和 有助于开发新的基于大脑区域的方法， 吸毒成瘾的问题。

Despite intensive effort to understand the brain substrates of cocaine addiction through biochemical investigations in the experimental animal, the cause of cocaine addiction remains unknown. We suggest that such neurochemical studies should also be conducted in brain of the human cocaine user. In an autopsied brain study of ten cocaine users, we observed reduced concentration of a specific neurotransmitter, dopamine (DA), in the nucleus accumbens--a brain area suggested to be involved in mediating both the acute and long-term effects of cocaine. The SPECIFIC AIMS of our proposed investigation are to examine the reliability and reversibility, cause, and drug and neurochemical specificities of the DA reduction. Our major HYPOTHESIS to be tested is that withdrawal from cocaine and other drugs of abuse will be associated with reductions in levels of nucleus accumbens DA, DA biosynthetic enzymes, and DA transporter, that are eventually reversed. This hypothesis will be tested through biochemical examination, by HPLC, Western Blot, and autoradiographic approaches, of levels of DA, the DA biosynthetic enzymes tyrosine hydroxylase and DOPA decarboxylase, and the DA transporter in autopsied brain of a minimum of ten cocaine, five opiate, five methamphetamine, and five alcohol users during each of the three years of our investigation. A special feature of this study is our ability to obtain, from U.S. medical examiners, autopsied brain of drug users characterized with respect to drug type, duration, and pattern. We expect that the results of our investigation will provide a robust test of the "DA depletion hypothesis of cocaine addiction" and, at the same time, will address the important medical issue of cocaine toxicity to human brain DA neurones. Ultimately, this information will help to clarify the contribution of the nucleus accumbens DA system to the behavioral consequences, and possibly causes, of cocaine use in the human and contribute to the development of new brain region-based approaches to the problem of drug addiction.