Cocaine-Molecular Targets/Brain Imaging and Medications

描述：(申请人提供)： 本申请NIDA高级科学家奖(K05)请求支持 寻求以药物滥用为重点的多学科计划的候选人 研究。候选人的总体目标是研究分子 精神刺激性药物滥用的靶点、神经适应机制 导致慢性药物暴露并开发新的和有效的 治疗可卡因成瘾的药物。多巴胺转运体，一个主要的目标 可卡因和安非他明，是研究的主要重点。这项研究 计划基于前一项目期间产生的激动人心的销售线索 并得到NIDA的两笔赠款和两份分包合同的支持。一个正在进行的 目的是研究新型可卡因激动剂的治疗潜力。 靶向多巴胺转运体，具有分子、生化、行为 和脑成像技术。非胺，和“马匹”是主要的 药物开发研究的重点。非胺类不含胺 它们结构中的氮仍然保持了对单胺的高亲和力 转运体和适当的大脑分布，它们的胺前体。 “托烷马”是一类新型化合物，被设计为可卡因拮抗剂。 脑多巴胺转运蛋白的PET成像将监测多巴胺转运蛋白 占用候选药物以确定完全阻断的药物剂量 可卡因进入运输车。细胞和分子生物学方法 将为我们的研究提供一个机械化的平台。我们会 研究多巴胺转运体基因多态性与 精神刺激剂诱发的行为反应及其影响 多巴胺转运体密度的多态性。底物或抑制剂诱导 在转染多巴胺的细胞中的即刻早期基因表达 Transporter将指导对神经适应过程的平行研究 突触前多巴胺神经元。这项研究将在细胞系中进行 通过灵长类转运蛋白和非人类灵长类动物。这 综合研究计划将提供有关 行为效应背后的神经生物学机制 治疗可卡因成瘾的精神刺激剂和候选药物。

DESCRIPTION: (Provided by Applicant): This application for a NIDA Senior Scientist Award (K05) requests support for the candidate to pursue a multidisciplinary program focused on drug abuse research. The candidate's overall objectives are to investigate the molecular targets of psychostimulant drugs of abuse, the neuroadaptive mechanisms consequent to chronic drug exposure and to develop novel and effective medications for cocaine addiction. The dopamine transporter, a principal target of cocaine and amphetamine, is the major focus of the research. The research program is based on exciting leads generated over the previous project period and is supported by two grants from NIDA and two subcontracts. An ongoing objective is to investigate the therapeutic potential of novel cocaine agonists targeted to the dopamine transporter, with molecular, biochemical, behavioral and brain imaging techniques. Non-amines, and "tropane horses" are a major focus of the medications development research. Non-amines bear no amine nitrogen in their structure yet retain the high affinity for the monoamine transporters and appropriate brain distribution, of their amine progenitors. "Tropane horses" are a new class of compounds designed as cocaine antagonists. PET imaging of brain dopamine transporters will monitor dopamine transporter occupancy of candidate medications to establish drug doses that fully block access of cocaine to the transporter. Cell and molecular biology approaches will provide a mechanistic platform in support of our research. We will investigate the relevance of dopamine transporter gene polymorphisms to behavioral responses elicited by psychostimulants and the influence of polymorphisms on dopamine transporter density. Substrate or inhibitor induction of immediate early gene expression in cells transfected with the dopamine transporter will guide parallel investigation of neuroadaptive processes in pre-synaptic dopamine neurons. The research will be conducted in cell lines transfected with primate transporters and in non-human primates. This integrated research program will provide fundamental information on the neurobiological mechanisms underlying the behavioral effects of psychostimulants and candidate medications to treat cocaine addiction.