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，并有助于找到治疗这种和 其他精神障碍。多巴胺、5-羟色胺和 去甲肾上腺素(DAT、SERT和NET)是可卡因的高亲和力靶标， 安非他明和几种治疗精神障碍的重要治疗药物。 这是假设和普遍接受的成瘾特性 可卡因主要由DAT介导。这一假设的基础是 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及其结构基础的研究 属性。2)确定克隆的转运蛋白中的区域或残基 都参与了可卡因的结合并研究了结合的性质 相互作用，以及3)设计一种功能类似于 野生型(Wt)小鼠DAT(MDAT)，但可卡因含量有显著变化 敏感度。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。在数百万年的进化过程中，自然界 产生了大量的功能转运蛋白变体，展示了 运输性质以及对可卡因和其他药物的敏感性的差异 药物为造成这种差异的残留物提供了线索。我们会 从不同物种克隆DAT、SERT和NET，包括一种毛虫害虫 利用已知序列信息进行聚合酶链式反应的古柯植物 传送者。我们将确定在运输的各个方面涉及的残留物 功能及与可卡因等药物结合的比较克隆 传送者。我们将在附近进行特定和随机的突变 与可卡因结合有关的残基和功能突变体的筛选 对可卡因不那么敏感的人。转基因小鼠产生 突变的DAT将使我们能够测试DAT在药物添加中的作用。一目了然 了解转运蛋白如何发挥作用，药物如何结合以及在哪里结合 转运体，DAT，SERT和Net在药物成瘾中的作用是重要的 用于开发新的、更有效的药物成瘾和其他治疗方法 精神错乱。

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.