Molecular Studies of Cocaine Action in Brain

项目摘要 这项R01拨款旨在更好地了解慢性接触的分子机制 滥用药物会导致大脑奖赏回路的长期变化，从而导致复杂的 定义成瘾状态的行为异常。我们的工作重点是转录因子AFosB， 它是在伏核(NAC)和其他关键的大脑奖赏区域诱导的，以响应慢性 管理几乎所有的滥用药物。AFosB的独特之处在于它只积累到可察觉的水平 在长期接触药物后，由于其不同寻常的稳定性，可持续数周至数月的戒断。 因此，AFosB是慢性药物暴露可以驱动基因长期变化的一种机制 导致上瘾的表情。事实上，相当多的证据支持这样一种观点，即诱导 NAC的AFosB调节一种高奖励和动机的状态，这可能有助于在某些方面 上瘾的过程。在这次请求的R37续订中，我们将描述通过以下方式实现的精确机制 AFosB执行这些操作。使用最先进的全基因组染色质分析，我们将在 在可卡因和鸦片类药物自我给药的背景下，NAC是AFosB的直接目标。这样的基因， 反过来，为药物诱导的神经和行为的分子和细胞基础提供了新的见解 可塑性。有趣的是，当AFosB与其目标基因结合时，它可以激活或抑制它们。我们的 假说是，这种激活和抑制作用是由受影响的染色质环境决定的。 吉恩。此外，在NAC中，部分不重叠的基因受到AFosB的调控，对这两种药物做出反应。 尽管这可能部分是通过药物诱导的部分不同的神经元亚群来调节的 AFosB，我们再次假设这种特异性也部分地通过其他染色质的差异来调节 可卡因和鸦片类药物在特定基因上引起的变化。除了探索AFosB对靶标的调控 基因，我们还将描述几种在决定酶的数量和活性方面至关重要的机制。 在NAC中诱导出AFosB。总而言之，这些研究将确定许多新的滥用药物行为， 可用于开发改进的成瘾诊断测试和治疗方法。

Project Summary 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, AFosB, 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. AFosB 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. AFosB 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 AFosB in NAc mediates a state of heightened reward and motivation that could contribute to aspects of the addiction process. In this requested R37 renewal, we will characterize the precise mechanisms through which AFosB 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 AFosB in the context of cocaine and opiate self-administration. Such genes, in turn, provide novel insight into the molecular and cellular basis of drug-induced neural and behavioral plasticity. Interestingly, when AFosB 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, partially non-overlapping genes are regulated by AFosB in NAc in response to the two drugs. Although this is likely mediated in part by the partly distinct subsets of neurons in which the drugs induce AFosB, we once again hypothesize that this specificity is also mediated partly by differences in other chromatin changes that cocaine and opiates induce at specific genes. In addition to exploring AFosB's regulation of target genes, we will also characterize several mechanisms that are crucial in determining the amount and activity of AFosB 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.