The Role of the Neurokinin-1 Receptor and NF kappa B in alcohol-induced behavior

酗酒是一种影响数百万美国人生活的严重疾病，但成功的治疗 一直难以捉摸。一些药物目前被批准用于治疗，但它们缺乏广泛的疗效， 在某些情况下，这是由于药物遗传相互作用造成的。未来的研究必须继续确定 药物开发的潜在靶点，并解决影响疗效的因素 药物疗法。大脑应激系统会影响饮酒和寻酒 人类和动物模型。在啮齿动物中，暴露在压力下会导致P物质(SP)和 激活其神经激动素1受体(NK1R)，并阻断NK1R，抑制酒精寻求和 消费。NK1R拮抗剂在喜欢酒精的大鼠中的疗效增强，我们已经证明了这一点 有一个升级的NK1R系统。一个悬而未决的问题是，NK1R系统是否超敏 是酒精中毒的易感因素，是长期酒精暴露的结果，或者两者兼而有之。这项提议将 通过确定长期饮酒后NK1R的表达是否增加来直接解决这个问题 暴露，这与对NK1R拮抗敏感的酒精寻求行为增加有关。 这些实验的结果将对临床治疗产生重大影响，因为他们将确定 NK1R拮抗对大多数有长期滥用史的酗酒者是有益的，或者如果 这种药物将仅限于表现出NK1R过敏的一部分人群。 虽然NK1R在饮酒和饮酒中的作用是有据可查的，但人们对NK1R的了解较少 潜在的细胞内信号机制。NK1R诱导转录因子核的活性 Kappa B因子(NFkB)是一种转录调节剂，调节多种基因的转录。这 转录因子在啮齿类动物中被应激源和酒精激活，因此是一个有趣的靶点 影响NK1受体介导的应激-酒精相互作用。在这里概述的研究中，我将首先描述 酒精暴露后NK1R和NFkB激活的关系及其下游的确定 这种相互作用产生的行为影响，如戒断焦虑和酒精奖励。NK1R和 NFkB还调节吗啡诱导的行为，这表明针对这些系统的药物可能是 对酒精、鸦片类药物和多种物质滥用的有效治疗。这具有重要的治疗意义， 因为多物质滥用在药物依赖者中非常普遍。 作为过渡赠款，培训是K99阶段的一个主要组成部分。除了研究之外， 目标如上所述，这项建议是为了促进我从博士后导师的过渡 从研究员到独立、终身教职的学术机构的研究人员。在接受指导的过程中 阶段，1学习了分子生物学的新技术，包括电迁移移位分析，这将增强 我从多个层面回答科学问题的能力。除了这次重要的科学训练，我还收获了 具有项目管理、学生辅导、助学金撰写和科学交流方面的经验。这个 这笔赠款的指导阶段非常成功，结果出版了几份同行评审的 手稿，提供有益的培训，并帮助我建立-为未来的成功。的主要目标是 导师的一年是为了获得终身教职跟踪助理教授的职位，这一点已经实现了。在……里面 2014年1月，1将开始担任生理系助理教授和 佐治亚大学的药理学。

Alcoholism is a serious condition that affects the lives of millions of Americans, but successful treatment has been elusive. Some medications are currently approved for treatment, but they lack widespread efficacy, which in some cases is due to pharmacogenetic interactions. Future research must continue to identify potential targets for medications development, and address factors that influence response to pharmacotherapy. Brain stress systems can influence alcohol consumption and alcohol seeking in both humans and animal models. In rodents, exposure to stress results in the release of substance P (SP) and activation of its neurokinin 1 receptor {NK1R), and NK1R blockade suppresses alcohol seeking and consumption. The efficacy of NK1R antagonists is enhanced in alcohol preferring rats, which we have shown to have an upregulated NK1R system. One outstanding question is whether this NK1R system hypersensitivity is a predisposing factor for alcoholism, results from chronic alcohol exposure, or both. This proposal will directly address this question by determining if NK1R expression is increased following chronic alcohol exposure, and rf this associates with increased alcohol seeking behavior that is sensitive to NK1R antagonism. The findings of these experiments will have a significant impact on clinical treatment, as they will identify if NK1R antagonism would be beneficial for most alcoholics with long term history of abuse, or if the efficacy of this drug would be confined to a portion of the population that exhibits NK1R hypersensitivity. While the role of NK1R in alcohol seeking and consumption is well documented, less is known about underlying intracellular signaling mechanisms. The NK1R induces the activity of the transcription factor Nuclear Factor kappa B (NFkB), which serves as a transcriptional modulator for a wide range of genes. This transcription factor is activated in rodents both by stressors and alcohol, and therefore is an intriguing target for influencing NK1 R-mediated stress-alcohol interactions. In the studies outlined here, I will first describe the relationship between NK1R and NFkB activation following alcohol exposure, and determine the downstream behavioral effects that result from this interaction, such as withdrawal anxiety and alcohol reward. NK1R and NFkB also regulate morphine-induced behaviors, suggesting that agents targeting these systems could be useful treatments for alcohol, opiate, and polysubstance abuse. This has important therapeutic implications, since polysubstance abuse is very common in drug dependent individuals. As a transition grant, training was a major component of the K99 phase. In addition to the research aims described above, this proposal was designed to facilitate my transition from mentored post-doctoral research fellow to independent, tenure track research faculty at an academic institution. During the mentored phase, 1 learned new techniques in molecular biology including electromobility shift assays, which will enhance my ability to answer scientific questions on multiple levels. Outside of this important scientific training, I gained experience in project management, student mentorship, grant writing, and scientific communication. The mentored phase of this grant was highly successful, resulting in the publication of several peer-reviewed manuscripts, providing beneficial training, and helping to set me up -for future success. A primary goal of the mentored year was to obtain a tenure track assistant professor position, and this was accomplished. In January 2014,1 will begin a position as an Assistant Professor in the Department of Physiology and Pharmacology at the University of Georgia.