Mechanism of drug addiction

描述（由申请人提供）：我们的长期目标是了解 药物成瘾的机制，并有助于找到治愈这一点， 其他精神障碍。多巴胺，血清素， 去甲肾上腺素（DAT、SERT和NET）是可卡因的高亲和力靶标， 安非他明和几种重要的治疗精神疾病的药物。 人们假设并普遍接受的是， 可卡因主要由DAT介导。这一假设是基于 间接证据。我们的具体目标是：1）克隆生物胺 不同物种的转运蛋白，并研究转运的结构基础 特性. 2)以鉴定克隆转运蛋白中的区域或残基， 参与可卡因的结合，并研究这种结合的性质 相互作用，和3）工程改造一个突变体DAT，其功能类似于 野生型（wt）小鼠DAT（mDAT），但可卡因中有实质性变化 灵敏度我们未来的目标是培育出携带突变基因的转基因小鼠 DAT与可卡因敏感性的变化，并确定DAT在 可卡因引起的反应经过数百万年的进化，大自然 产生了大量的功能性转运蛋白变体， 运输特性和对可卡因和其他毒品的敏感性的差异 药物提供线索的残留物负责的差异。我们将 克隆DAT，SERT和NET从不同的物种，包括毛虫害虫 使用已知的古柯植物的序列信息通过聚合酶链反应 运输机我们将确定参与运输各个方面的残留物 功能和结合可卡因和其他药物，通过比较克隆 运输机我们将在和附近的特定和随机突变， 参与可卡因结合的残基，并筛选功能突变体 对可卡因的敏感性明显降低。转基因小鼠 突变的DAT将使我们能够测试DAT在药物添加中的作用。一个明确 了解转运蛋白如何发挥作用，药物如何以及在何处与 转运蛋白，DAT，SERT和NET在药物成瘾中的作用是重要的 开发新的和更有效的治疗药物成瘾和其他 精神障碍

DESCRIPTION (provided by applicant): Our long-term goal is to understand the mechanism of drug addiction and to contribute to finding cures for this and other mental disorders. The transporters for dopamine, serotonin, and norepinephrine (DAT, SERT, and NET) are the high affinity targets for cocaine, amphetamines and several important therapeutic drugs treating mental disorders. It was hypothesized and generally accepted that the addictive property of cocaine is mediated predominantly by DAT. This hypothesis has been based on indirect evidence. Our specific aims are 1) to clone biogenic amine transporters from diverse species and to study structural basis of transport properties. 2) to identify regions or residues in the cloned transporters that are involved in cocaine binding and to study the nature of the binding interactions, and 3) to engineer a mutant DAT that is functionally similar to wild type (wt) mouse DAT (mDAT) but with a substantial shift in cocaine sensitivity. Our future aims are to generate transgenic mice bearing a mutant DAT with a shift in sensitivity to cocaine and to determine the role of DAT in cocaine-induced responses. Over millions of years of evolution, nature has generated a large number of functional transporter variants exhibiting differences in transport properties and in the sensitivity to cocaine and other drugs providing clues to the residues responsible for the differences. We will clone DAT, SERT, and NET from diverse species including a caterpillar pest of coca plant by polymerase chain reaction using the sequence information of known transporters. We will identify residues involved in various aspect of transport function and in binding cocaine and other drugs by comparing cloned transporters. We will make specific and random mutations at and near the residues that are involved in cocaine binding and screen for functional mutants that are significantly less sensitive to cocaine. Transgenic mice bearing mutant DAT will allow us to test the role of DAT in drug addition. A clear understanding of how transporters function, how and where drugs bind to the transporters, and the role of DAT, SERT, and NET in drug addiction is important for developing new and more effective treatments for drug addiction and other mental disorders.