Molecular Studies of Cocaine Action in Brain

可卡因大脑作用的分子研究

• 批准号: 8240424
• 负责人: ERIC J. NESTLER
• 金额: $ 52.82万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240424
• 关键词: Acute; Affect; Behavioral; Binding; Biochemical Pathway; Biological; Biological Assay; Brain; Brain region; Chromatin; Chronic; Cocaine; Complex; Corpus striatum structure; Dendritic Spines; Development; Diagnostic tests; Dorsal; Dose; Drug Addiction; Drug Exposure; Exposure to; FOS gene; Gene Expression; Gene Proteins; Gene Targeting; Genes; Genomics; Goals; Grant; Injection of therapeutic agent; Investigation; Left; Mediating; Methods; Molecular; Motivation; Neurons; Nucleus Accumbens; Opiates; Pattern; Pharmaceutical Preparations; Phenotype; Phosphorylation; Plastics; Post-Translational Regulation; Process; Progress Reports; Property; Protein Family; Protein Isoforms; Protein Kinase; Proteins; Publishing; Regulation; Research; Rewards; Role; Self Administration; Series; Specificity; Stimulus; Time; Withdrawal; Work; addiction; base; cell type; drug of abuse; drug withdrawal; genome wide association study; genome-wide; improved; innovation; insight; interest; neuromechanism; novel; public health relevance; relating to nervous system; response; transcription factor

DESCRIPTION (provided by applicant): This R01 grant is aimed at better understanding the molecular mechanisms by which chronic exposure to drugs of abuse induces long-lasting changes in the brain's reward circuits that contribute to the complex behavioral abnormalities that define an addicted state. Our work focuses on the transcription factor, FosB, which is induced in the nucleus accumbens (NAc) and other key brain reward regions in response to chronic administration of virtually all drugs of abuse. FosB is unique in that it accumulates to appreciable levels only after chronic drug exposure and, because of its unusual stability, persists for weeks-months of withdrawal. FosB is thus one mechanism by which chronic drug exposure can drive long-lasting changes in gene expression that contribute to addiction. Indeed, considerable evidence supports the view that induction of FosB in NAc mediates a state of heightened reward and motivation that could contribute to aspects of the addiction process. In this competitive renewal, we will characterize the precise mechanisms through which FosB exerts these actions. Using state-of-the-art genome-wide chromatin assays, we will identify the genes in the NAc that are direct targets for FosB in the context of cocaine and opiate administration. Such genes, in turn, provide novel insight into the molecular and cellular basis of drug-induced neural and behavioral plasticity. Interestingly, when FosB binds to its target genes, it can either activate or repress them. Our hypothesis is that such activation vs. repressive actions are determined by the chromatin milieu of the affected gene. As well, despite the fact that cocaine and opiates induce FosB in the same subtype of NAc neuron, partially non-overlapping genes are regulated by FosB in response to the two drugs. Once again, our hypothesis is that this specificity is mediated by differences in other chromatin changes that cocaine and opiates induce at specific genes. In addition to exploring FosB's regulation of target genes, we will also characterize several mechanisms that are crucial in determining the amount and activity of FosB induced in the NAc. Together, these studies will identify many novel actions of drugs of abuse which can be exploited for the development of improved diagnostic tests and treatments for addiction. PUBLIC HEALTH RELEVANCE: We believe that the best way to ultimately develop improved diagnostic tests and treatments for drug addiction is through a better understanding of the basic biological mechanisms involved. This R01 grant renewal will contribute importantly to this goal by defining many novel genes and proteins, and therefore novel biochemical pathways and neural mechanisms, involved in the addiction process.

描述（由申请人提供）：这项 R01 资助旨在更好地了解长期接触滥用药物会导致大脑奖励回路发生长期变化的分子机制，从而导致定义成瘾状态的复杂行为异常。我们的工作重点是转录因子 FosB，它是在伏隔核 (NAc) 和其他关键大脑奖赏区域中诱导产生的，以响应几乎所有滥用药物的长期给药。 FosB 的独特之处在于，只有在长期接触药物后，它才会积累到可观的水平，并且由于其异常的稳定性，在停药后数周或数月内仍会持续存在。因此，FosB 是一种机制，通过这种机制，慢性药物暴露可以驱动导致成瘾的基因表达的长期变化。事实上，大量证据支持这样的观点，即 NAc 中 FosB 的诱导会介导一种更高的奖励和动机状态，这可能有助于成瘾过程的各个方面。在这次竞争更新中，我们将描述 FosB 发挥这些作用的精确机制。使用最先进的全基因组染色质检测，我们将鉴定 NAc 中的基因，这些基因是可卡因和阿片类药物施用中 FosB 的直接靶标。反过来，这些基因为药物诱导的神经和行为可塑性的分子和细胞基础提供了新的见解。有趣的是，当 FosB 与其靶基因结合时，它可以激活或抑制它们。我们的假设是，这种激活与抑制行为是由受影响基因的染色质环境决定的。同样，尽管可卡因和阿片类药物在相同亚型的 NAc 神经元中诱导 FosB，但部分不重叠的基因受到 FosB 的调节以响应这两种药物。我们的假设是，这种特异性是由可卡因和阿片类药物在特定基因上诱导的其他染色质变化的差异介导的。除了探索 FosB 对靶基因的调节之外，我们还将描述对于确定 NAc 中诱导的 FosB 的数量和活性至关重要的几种机制。总之，这些研究将确定滥用药物的许多新作用，可用于开发改进的成瘾诊断测试和治疗方法。 公共卫生相关性：我们相信，最终开发改进的毒瘾诊断测试和治疗方法的最佳方法是更好地了解所涉及的基本生物学机制。此次 R01 拨款更新将通过定义许多新的基因和蛋白质，从而定义参与成瘾过程的新的生化途径和神经机制，为这一目标做出重要贡献。