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。它主要影响 年轻人，摧毁生命。为了理解强化和激励 药物滥用方面，我们需要阐明生物和分子 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神经元发挥它们的成瘾特性。 系统反复滥用这些药物会导致长期的行为 药物成瘾、药物耐受和药物致敏的后果。这些 适应随着时间的推移而发展，在停止使用药物后持续很长时间， 并涉及多巴胺感受神经元的长期变化。生物 这些变化的底物必须在这些药物对 基因表达。因为可卡因和安非他明在D1多巴胺 受体依赖方式，第二信使途径的研究 从D1受体的刺激到基因的表达， 药物成瘾的机制 本提案的目的是阐明D1处的信号如何 突触上的受体指导细胞核中的基因调节。我们假设 多巴胺激活了一系列导致去极化的因素， 与神经元内的第二信使一起， 表情 我们已经描述了一个模型系统的基因表达在初级纹状体 是由药物滥用激活的。在这个系统的帮助下， 信号级联的识别元素。的重要贡献者 我们实验室发现的多巴胺信号是N-甲基-D-天冬氨酸（NMDA） 受体的D1受体介导的基因表达被NMDA拮抗剂阻断， 并且依赖于功能性NMDA受体。目前尚不清楚双方如何 受体是偶联的。初步数据显示多巴胺会导致 NMDA受体NR 1亚型的磷酸化提供了潜在的 激活机制。我们现在建议进一步描述NR 1的作用 磷酸化可能在D1受体介导的基因表达中起作用。而且我们 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D1受体介导的基因表达依赖于 NMDA受体，我们将研究L型Ca 2+通道在D1 受体介导的基因表达。细胞内激酶的作用， 磷酸酶在D1受体介导的基因表达也将解决。 D1受体介导的信号级联反应的阐明对于 促进我们对药物成瘾机制的理解。此外，本发明还提供了一种方法， 有价值的见解，新的治疗策略，以防止或扭转 可以获得成瘾。

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.