Brain Biomarkers of Alcoholism and Abstinence

描述（由申请人提供）：本竞争性修订申请是为响应NOT-OD-09-058“NIH宣布恢复法案资金可用于竞争性修订申请”而提交的。家长资助的补助金是1 R 01 AA 016157，题为“酒精中毒和禁欲的大脑生物标志物”。酗酒是当今社会面临的最严重的问题之一。酒精中毒被定义为强迫性的、不受控制的使用乙醇，而不考虑身体或社会后果，以及在戒酒时复发的强烈倾向。在健康和社会混乱方面，社会的代价是巨大的。虽然我们对酒精中毒的理解已经取得了重大进展，但我们的知识还远远不够。需要进一步的研究来阐明相关机制。因此，实验的重点是阻断由使用毒品的压倒性需求和在没有毒品的情况下对毒品的强烈渴望所激发的行为的表达，这将对成瘾性毒品对健康和社会造成的损害产生更直接和更显著的影响。父母补助金的目标是：1）描绘大脑生物标志物，表明负责增加酒精摄入量的神经生物学机制; 2）定义与复发相关的大脑生物标志物。被测试的假设是：1）足够的酒精暴露导致扩展杏仁核的特定元素的变化，产生享乐设定点的升高。反过来，这导致乙醇摄入的进行性升高和戒断期间复发的倾向;和2）乙醇的自我给药与被动给药相结合引起蛋白质表达水平和功能的变化，比单独被动给药更具有成瘾过程的特征。旨在检验这些假设的具体目的是：1）检查乙醇依赖性对蛋白质表达和修饰的影响，重点是与乙醇强化相关的变化; 2）确定与再次暴露于乙醇后复发的脆弱性相关的蛋白质表达和修饰的长期变化。这项竞争性修订将通过调查和验证一种特别有前途的生物标志物血小板源性生长因子受体-β（PDGFR 2）来扩大我们的资助范围和目标。我们将测试一个全新的假设，即PDGFR 2拮抗剂可以逆转导致酗酒的神经可塑性。将通过实现以下具体目标来检验该假设：使用酒精中毒和复发的尖端大鼠模型，确定PDGFR 2拮抗作用对先前药物暴露后乙醇自我给药递增的影响。这组实验将把我们的资助提升到一个新的水平，迅速将它从一个“发现”项目转变为一个重点突出的假设测试提案。这是我们在撰写父母补助金时的长期目标。这一修订将使我们能够明显加快实现这一目标的进展，并创造新的就业机会和保留就业机会。我们还希望，这一独特和创新的建议最终将对酗酒问题产生重大影响，并给健康和社会带来重大惠益。 公共卫生相关性：酒精中毒是世界上最具破坏性的疾病之一。该项目包括一个全新的和非常有前途的酗酒生物标志物，血小板衍生生长因子受体β的行为和生化验证。我们将确定拮抗该受体对大鼠饮酒行为的影响。我们希望，这一独特和创新的建议将最终导致新的和更有效的治疗酗酒的战略。

DESCRIPTION (provided by applicant): This Competitive Revision Application is submitted in response to NOT-OD-09-058, "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications". The parent funded grant is 1R01AA016157, entitled "Brain Biomarkers of Alcoholism and Abstinence". Alcoholism is one of the most overwhelming problems facing society today. Alcoholism has been defined as the compulsive, uncontrolled use of ethanol regardless of the physical or social consequences, as well as a strong tendency to relapse when abstinent. The cost to society, in terms of both health and social disruption is enormous. While significant advances in our understanding of alcoholism have been made, our knowledge is far from complete. Much further research is needed to elucidate the mechanisms responsible. Thus, an experimental focus on blocking the expression of behaviors motivated by the overwhelming need to use drugs and the intense craving for drugs in their absence would have a more immediate and dramatic impact on the damage to health and society caused by addictive drugs. The goals of the parent grant are: 1) to delineate brain biomarkers that indicate the neurobiological mechanisms responsible for increased alcohol intake; and 2) to define brain biomarkers associated with relapse. The hypotheses being tested are: 1) Sufficient exposure to alcohol leads to changes in specific elements of the extended amygdala that produce elevations in the hedonic set point. In turn, this leads to progressive elevation in ethanol intake and a propensity to relapse during abstinence; and 2) Self-administration of ethanol coupled with passive administration causes changes in protein expression levels and function more characteristic of the addictive process than passive administration alone. The Specific Aims designed to test these hypotheses are: 1) To examine the effects of ethanol dependence on protein expression and modification with a focus on changes associated with ethanol reinforcement; and 2) To determine long-lasting changes in protein expression and modification associated with vulnerability to relapse upon re-exposure to ethanol. This competitive revision will expand the scope and objectives of our grant by investigating and validating a particularly promising biomarker, platelet-derived growth factor receptor-beta (PDGFR2). We will test a completely new hypothesis, that PDGFR2 antagonism can reverse the neuroplasticity that drives alcoholism. This hypothesis will be tested by accomplishing the following Specific Aim: Determining the effect of PDGFR2 antagonism on the escalation of ethanol self- administration after previous drug exposure using a cutting-edge rat model of alcoholism and relapse. This set of experiments will take our grant to the next level, rapidly transforming it from a "discovery" project into a focused, hypothesis-testing proposal. This was our long-term objective when writing the parent grant. This revision would enable us to markedly accelerate our progress toward this objective, as well as creating new jobs and permitting job retention. We also hope that this unique and innovative proposal will ultimately have a major impact on the problem of alcoholism and result in major benefits for health and society. PUBLIC HEALTH RELEVANCE: Alcoholism is one of the most devastating diseases in the world. This project consists of the behavioral and biochemical validation of a completely new and very promising biomarker of alcoholism, the platelet-derived growth factor receptor-beta. We will determine the effect of antagonizing this receptor on alcohol drinking behavior in rats. We hope that this unique and innovative proposal will ultimately lead to new and more effective treatment strategies for alcoholism.