CORE--CHEMISTRY

化学核心将合成用于可卡因成瘾生物学研究的新型分子探针，这些探针将用于该中心内的各种项目和试点项目。这些分子探针将使该中心能够探索有关可卡因成瘾的中心问题。阻断单胺转运蛋白的“化学敲除”将被产生，并用于研究可卡因的敏化作用。选择性5-羟色胺转运体(SERT)抑制剂将被用来研究SERT抑制对可卡因成瘾的作用。新的神经显像剂将被用于研究多巴胺转运体(DAT)和SERT在大脑中的神经化学变化。将制备不同官能化的放射性标记的不可逆配体来研究DAT抑制剂的结合部位。 化学核心将与该中心的几乎所有其他项目互动。与以下项目交互 子项目0001(Childers)将非常广泛，因为子项目0001的一个主要组成部分将是使用所有放射性标记的不可逆抑制剂来绘制DAT图。有希望的不可逆抑制剂也将在子项目0005(Smith/Martin)中进行行为评估。子项目0008(Vrana)将探索长效托品对特定基因表达的影响，重点是连接蛋白。子项目0011(罗伯茨)的一个组成部分将是探索可卡因使用的慢性化如何影响局部效应和大脑中的连接蛋白。长效托烷将是这一项目有用的分子工具。将为PET成像核心准备每个放射性配体的前体，这些前体将用于分项目0012(波里诺)和0009(纳德)。在涉及试点项目的合作研究中提出了开发新的放射性配体。项目7的一个主要组成部分是调查具有SERT选择性的化学核心化合物选择性减少恒河猴体内可卡因自我给药的能力。

The Chemistry Core will synthesize novel molecular probes for biological studies on cocaine addiction that will be available for the various projects and pilot projects within the Center. These molecular probes will enable the Center to explore central questions regarding cocaine addiction. "Chemical knockouts" blocking the monoamine transporters will be generated and used to study cocaine sensitization. Selective serotonin transporter (SERT) inhibitors will be used to study the role of the SERT inhibition on cocaine addiction. New neuroimaging agents will be generated to study dopamine transporter (DAT) and SERT neurochemical changes in the brain. Differentially functionalized radiolabeled irreversible ligands will be prepared to study the binding sites of DAT inhibitors. The Chemistry Core will interact with virtually all the other projects in the Center. Interaction with subproject 0001 (Childers) will be very extensive because a major component of subproject 0001 will be the use ol radiolabeled irreversible inhibitors to map the DAT. Promising irreversible inhibitors will also be evaluated behaviorally in subproject 0005 (Smith/Martin). Subproject 0008 (Vrana) will be exploring the effects of long acting tropanes on specific gene expression, with emphasis on connexins. One component of subproject 0011 (Roberts) will be the exploration of how the chronisity of cocaine administration impacts regional effects and connexin proteins in the brain. Long acting tropanes will be useful molecular tools for this project. Precursors to PEr radioligands will be prepared for the PET Imaging Core and these will be used in subProject 0012 (Porrino) and 0009 (Nader). The development of new radioligands is proposed in collaborative studies involving the Pilot Projects. A major component of Project 7 is to investigate the ability of compounds from the Chemistry Core with selectivity for SERT to selectively decrease cocaine self-administration in rhesus monkeys.