Dopamine Transporter--Structure/function Studies Of Tran

多巴胺转运体（DAT）是一个主要的脑受体部位，与可卡因的奖赏和欣快特性相关。MNB科学家克隆了DAT cDNA和基因，发现DAT和SERT的缺失是消除小鼠可卡因条件位置偏好所必需的。DAT是目前产生帕金森病最佳模型的每种多巴胺选择性毒素的作用所必需的。DAT结构-功能关系及其与通过5-羟色胺受体亚型定义的5-羟色胺系统的关系的分析在今年继续进行。从往年的工作有关多巴胺转运蛋白和小分子底物和配体的结构/功能关系的报告在这一年。我们还报道了启动子区单倍型的进一步表征及其在体内表达水平变化中的作用。研究以我们报告的与1）成像中体内DAT表达水平和2）死后人纹状体样品中鉴定的DAT表达水平相关的方式改进了5 'DAT单倍型的定义。DAT、5 HT 1A和5 HT 1B受体改变的“三重敲除”小鼠对可卡因奖赏产生了影响，这在单敲除或双敲除小鼠中没有发现。这些见解应继续有助于识别DAT调控相关的结构-功能关系，以及DAT表达水平和药理学的人类个体差异。

The dopamine transporter (DAT) has been a principal brain receptor site that has been correlated with the rewarding and euphoric properties of cocaine. MNB scientists cloned the DAT cDNA and gene, and found that deletion of both DAT and SERT are required to eliminate cocaine conditioned place preferences in mice. DAT is required for the actions of each of the current dopamine-selective toxins that produce the best models of Parkinson's disease. Analyses of DAT structure- function relationships, and their relationships with serotonin systems defined through the serotonin receptor subtypes, continued during this year. Work from prior years concerning structure/function relationships of the dopamine tranporter and small molecule substrates and ligands was reported during the year. We also reported further characterization of promoter region haplotypes and their roles in level of expresion variation in vivo. Studies refined the definition of the 5'DAT haplotypes in ways that we reported to correlate with 1)levels of DAT expression in vivo in imaging and 2) levels of DAT expression identified in postmortem human striatal samples. "Triple knockout" mice with alterations of DAT, 5HT1A and 5HT1B receptors produced effects on cocaine reward not identified in single- or double-knockout mice. These insights should continue to help in identification of structure-function relationships relevant to DAT regulation and human individual differences in DAT levels of expression and pharmacology.