DRUG RECEPTORS, NEUROTRANSMITTERS AND ADDICTION

药物受体、神经递质和成瘾

• 批准号: 3775017
• 负责人: M J KUHAR
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3775017
• 关键词: cocaine; corpus striatum; dopamine; drug addiction; drug receptors; drug withdrawal; gene expression; in situ hybridization; laboratory rat; membrane transport proteins; messenger RNA; neuropharmacology; nucleus accumbens; receptor binding

The focus of this project is to elucidate mechanisms involved in the repetitive use of drugs, the long-term effects of drugs and the biochemical mechanisms underlying chronic drug taking and drug seeking behavior. In a series of studies, we treated animals with cocaine in a long-term, but intermittent fashion. The pattern of administration was similar to that observed in animals self-administering cocaine. We utilized Lewis rats as they show a propensity for self administering cocaine compared to other strains. We found that, after 10 days of withdrawal, there was a significant decrease in dopamine transporter (a cocaine receptor) binding in the nucleus accumbens but not in the striatum. The decrease in transporter binding in the accumbens was long- lasting and still apparent by 60 days after withdrawal. Thus, there is a long-lasting change in dopamine transporter in limbic areas which appears during the withdrawal period and which is persistent. This type of biochemical phenomena could be related to long-term effects of drugs in human populations. In an effort to elucidate the mechanism of this down regulation of transporter, we carried out an in situ hybridization study in collaboration with Dr. George Uhl. We found a significant reduction in dopamine transporter MRNA in midbrain cell groups that project to the nucleus accumbens. Changes in MRNA were not found in cell groups projecting to the striatum. These data indicate that changes in gene expression can occur during drug withdrawal and also that regulation of the dopamine transporter can involve a change in gene expression. Taken together, we have carried out a series of successful studies in changes in the dopamine transporter during chronic drug administration and withdrawal.

该项目的重点是阐明参与的机制， 药物的长期影响和药物的长期使用 慢性吸毒和寻求毒品的生化机制 行为 在一系列的研究中，我们用可卡因治疗动物， 长期但间歇性的 给药方式为 类似于在动物自我施用可卡因中观察到的。 我们 利用刘易斯大鼠，因为它们表现出自我给药的倾向 可卡因与其他品种相比。 我们发现，10天后， 停药后，多巴胺转运蛋白（a 可卡因受体）结合在丘脑核中，而不是在 纹状体 受体结合的减少是长期的- 停药后60天仍然明显。因此， 大脑边缘区多巴胺转运蛋白的长期变化， 在停药期出现，并且持续存在。 这种类型 可能与药物的长期作用有关 在人类群体中。 为了阐明这种下调的机制， 转运蛋白，我们进行了原位杂交研究， 与乔治乌尔博士合作。 我们发现， 中脑细胞群中的多巴胺转运蛋白mRNA， 丘脑核细胞组mRNA水平无明显变化 投射到纹状体。这些数据表明， 表达可以发生在药物戒断期间， 多巴胺转运蛋白可能涉及基因表达的变化。 我们已进行了一系列成功的研究， 多巴胺转运蛋白在慢性给药过程中的变化 和撤退。