PSYCHOSTIMULANT REGULATION OF NEURAL GENE EXPRESSION

描述：(申请人摘要) 吸毒成瘾是发达国家的一个主要问题。它影响最大的是 会毁了年轻人的生活。理解强化和激励 在药物滥用方面，我们需要阐明生物学和分子方面的 在药物成瘾中起作用的机制。 可卡因和安非他明通过多巴胺能发挥其成瘾特性 系统。反复滥用这些药物会导致长期的行为 药物成瘾、药物耐受性和药物敏感化的后果。这些 适应随着时间的推移而发展，在戒毒后很长一段时间内持续存在， 并涉及多巴胺感受性神经元的长期变化。生物学的 必须寻找这些变化的根源，以了解这些药物对 基因表达。因为可卡因和安非他明在多巴胺中起作用 受体依赖方式，第二信使途径的研究 从D1受体刺激到基因表达可以为我们提供洞察力 关于药物成瘾的机制。 这项建议的目的，是要澄清首长级薪级表的讯号是如何 突触上的受体指导核内的基因调控。我们假设 多巴胺激活了一系列导致去极化和 与神经元内的第二信使一起，影响基因 表情。 我们描述了一个初级纹状体基因表达的模型系统 因滥用药物而被激活的文化。在这个系统的帮助下，我们有了 确定了信令级联的元素。一个重要的贡献者 我们实验室发现的多巴胺信号是N-甲基-D-天冬氨酸(NMDA)。 受体。D1R介导的基因表达被NMDA拮抗剂阻断， 并且依赖于功能上的NMDA受体。目前还不清楚两者是如何 受体是偶联的。初步数据显示，多巴胺导致 NMDA受体NR1亚型的磷酸化提供了一个潜在的 激活机制。我们现在建议进一步描述NR1的角色 磷酸化可能在D1受体介导的基因表达中起作用。此外，我们 将研究NMDA受体如何将多巴胺信号转导到 神经元核。 NMDA受体介导的基因表达分析表明， L型钙通道。由于D1R介导的基因表达依赖于 NMDA型受体，我们将研究L型钙通道在D1中的作用 受体介导的基因表达。细胞内激酶和蛋白的作用 磷酸酶在D1受体介导的基因表达中也将被讨论。 阐明D1R介导的信号级联对于 提高我们对药物成瘾机制的认识。此外, 对预防或逆转的新治疗策略的宝贵见解 上瘾可能会上瘾。

DESCRIPTION: (Applicant's Abstract) Drug addiction is a major problem in the developed world. It affects mostly young people and destroys lives. To understand the reinforcing and motivational aspects of drug abuse, we need to elucidate the biological and molecular mechanisms that are at work in drug addiction. Cocaine and amphetamine exert their addictive properties via the dopaminergic system. Repeated abuse of these drugs causes the long-term behavioral consequences of drug addiction, drug tolerance, and drug sensitization. These adaptations develop over time, persist long after the cessation of drug use, and involve long-term changes in dopaminoceptive neurons. The biological substrate of these changes must be searched in the effect these drugs have on gene expression. Since cocaine and amphetamine work in a D1 dopamine receptor-dependent manner, the investigation of the second messenger pathway from D1 receptor stimulation to gene expression can provide us with insights into the mechanism of drug addiction. The goal of the present proposal is to elucidate how the signal at the D1 receptor at the synapse directs gene regulation in the nucleus. We hypothesize that dopamine activates a combination of factors that cause depolarization and that, altogether with second messengers inside the neuron, effect gene expression. We have characterized a model system of gene expression in primary striatal cultures that is activated by drug abuse. With the help of this system we have identified elements of the signaling cascade. An important contributor to dopamine signaling identified in our lab is the N-methyl-D-aspartate (NMDA) receptor. D1 receptor-mediated gene expression is blocked by NMDA antagonists, and is dependent on functional NMDA receptors. It is not clear how both receptors are coupled. Preliminary data that show that dopamine causes phosphorylation of the NR1 subtype of the NMDA receptor provide a potential mechanism of activation. We now propose to further characterize the role NR1 phosphorylation may play in D1 receptor-mediated gene expression. Moreover, we will investigate how the NMDA receptor transduces the dopamine signal to the neuronal nucleus. Analysis of NMDA receptor-mediated gene expression points to an involvement of L-type Ca2+ channels. Since D1 receptor-mediated gene expression depends on NMDA receptors, we will examine the role of L-type Ca2+ channels in D1 receptor-mediated gene expression. The role of intracellular kinases and phosphatases in D1 receptor-mediated gene expression will also be addressed. The elucidation of the D1 receptor-mediated signaling cascade is crucial to advance our understanding of the mechanism of drug addiction. In addition, valuable insight into novel therapeutic strategies to prevent or reverse addiction may be gained.