COCAINE SENSITIVE DOPAMINE TRANSPORTER SYNTHESIS

可卡因敏感多巴胺转运蛋白合成

• 批准号: 2733599
• 负责人: MICHAEL J KUHAR
• 金额: $ 24.54万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2733599
• 关键词: amphetamines; brain cell; brain metabolism; cocaine; dopamine agonists; dopamine antagonists; dopamine receptor; dopamine transporter; drug withdrawal; laboratory rat; methamphetamine; norepinephrine; protein biosynthesis; protein degradation; serotonin transporter; tissue /cell culture

the dopamine transporter is the target or "receptor" for psychostimulant drugs such as cocaine, amphetamine and methamphetamine. It is also the target or receptor for the therapeutic drug, methylphenidate, and the mediator of the neurotoxic effects of methamphetamine and MPTP. It is a unique marker for dopaminergic neurons and, imortantly, the mechanism of inactivation of released dopamine at the synapse. Moreover, administratio of drugs such a cocaine are known to alter the transporter levels indicating that it may be involved in regulating dopaminergic function in a dynmic way. Therefore, understanding the factors that regulate transporter levels is critical. The goal of this proposal is to elucidate these factors by; first, obtaining estimates of transporter synthesis rate and the degradatio rate consant in brain; second, measuring these after cocaine; and tird, identifying the role of dopamine receptor stimulation and/or dopamine levels in influencing synthesis and degradation. Since the brain is the organ of interest, these studies must be carried out in situ. But cells expressing the transporter are available and lend themselves to similar studies without the complexities of intact brain. Accordinaly will be carry out estimates of synthesis rate and degradation rate constant in cells in culture as well as studies of transporter movement of trafficking. This combined approach using both brain and cells in culture seems the most effective way to elucidate foctors controlling transporter synthesis, degradation and therefore levels. These studies will be lollowed up by identifying the molecular step(s) causing the changes in synthesis and degradation, and by suggesting new approaches for developing medications for drug abuseers.

多巴胺转运蛋白是靶点或受体， 精神兴奋剂药物，如可卡因、安非他明和 冰毒 它也是靶点或受体， 治疗药物哌醋甲酯及其介体 甲基苯丙胺和MPTP的神经毒性作用。 这是一个 多巴胺能神经元的独特标记物， 突触处释放的多巴胺失活的机制。 此外，已知药物如可卡因的施用 改变转运蛋白水平，表明它可能参与 以动态方式调节多巴胺能功能。 因此，我们认为， 了解调节转运蛋白水平的因素， 很危险 本提案的目的是阐明这些因素 首先，获得转运蛋白合成速率的估计值， 脑内降解速率常数;其次，测量这些 在可卡因之后;和第三，确定多巴胺受体的作用 刺激和/或多巴胺水平影响合成， 降解 由于大脑是感兴趣的器官，这些 研究必须在现场进行。 但是表达 转运蛋白是可用的，并适合于类似的研究 没有完整大脑的复杂性。 根据协议， 进行合成速率和降解速率的估算 在培养细胞中的恒定以及转运蛋白的研究 贩运的运动。 这种综合方法使用了 大脑和细胞的培养似乎是最有效的方法， 阐明控制转运蛋白合成、降解的因素 因此，水平。 这些研究将由 识别引起合成变化的分子步骤 和退化，并提出新的办法， 为吸毒者研发药物