Brain Biomarkers of Alcoholism and Abstinence

描述（由申请人提供）：本竞争性修订申请是为了响应NOT-OD-09-058，“NIH宣布竞争性修订申请的恢复法案资金可用性”而提交的。父母资助的基金是1R01AA016157，题为“酒精中毒和戒酒的大脑生物标志物”。酗酒是当今社会面临的最严重的问题之一。酗酒被定义为强迫性、不受控制地使用乙醇，不顾身体或社会后果，以及戒酒后复发的强烈倾向。就健康和社会混乱而言，对社会造成的代价是巨大的。虽然我们对酒精中毒的理解取得了重大进展，但我们的知识还远远不够完整。需要进一步的研究来阐明其机制。因此，将实验重点放在阻止由吸毒的迫切需要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上，将对成瘾药物对健康和社会造成的损害产生更直接和显著的影响。父母资助的目标是：1)描述大脑生物标志物，表明导致酒精摄入量增加的神经生物学机制；2)确定与复发相关的脑生物标志物。正在测试的假设是：1)充分接触酒精会导致扩展杏仁核的特定元素发生变化，从而产生享乐设定值的升高。反过来，这导致乙醇摄入量的逐渐升高和戒酒期间复发的倾向；2)与单独被动给药相比，乙醇自我给药联合被动给药引起的蛋白质表达水平和功能的变化更具有成瘾性。旨在验证这些假设的具体目的是：1)研究乙醇依赖对蛋白质表达和修饰的影响，重点关注与乙醇强化相关的变化；2)确定与再次暴露于乙醇后易感性复发相关的蛋白质表达和修饰的长期变化。这一竞争性修订将通过研究和验证一种特别有前途的生物标志物——血小板衍生生长因子受体- β (PDGFR2)，扩大我们资助的范围和目标。我们将测试一个全新的假设，即PDGFR2拮抗剂可以逆转导致酒精中毒的神经可塑性。这一假设将通过完成以下特定目的来验证：利用一种先进的酒精中毒和复发大鼠模型，确定PDGFR2拮抗剂对先前药物暴露后乙醇自我给药增加的影响。这一系列实验将把我们的拨款提升到一个新的水平，迅速将它从一个“发现”项目转变为一个有重点的、假设检验的提议。这是我们写家长补助金时的长期目标。这一修订将使我们能够显著加快实现这一目标的进程，同时创造新的就业机会，并允许保留就业机会。我们还希望，这一独特和创新的建议将最终对酗酒问题产生重大影响，并为健康和社会带来重大利益。

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.