Neuroimmune Interactions in High Alcohol Drinking

大量饮酒时的神经免疫相互作用

• 批准号: 8443114
• 负责人: SUSAN E. BERGESON
• 金额: $ 17.93万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443114
• 关键词: Adolescent; Adult; Affect; Alcohol consumption; Alcoholism; Alcohols; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Antibodies; Apoptosis; Applications Grants; Behavioral; Biology; Blood; Blood - brain barrier anatomy; Brain; Build-it; CD11b Antigens; Cells; Chemicals; Consumption; Data; Development; Dose; Ethanol; FDA approved; Future; Generations; Goals; ITGAM gene; Injection of therapeutic agent; Intoxication; Lead; Life; Macrophage-1 Antigen; Measures; Mediating; Microglia; Minocycline; Modification; Monoclonal Antibodies; Mus; Nature; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phenotype; Play; Population; Property; Proteins; Publishing; Rattus; Reagent; Regimen; Rewards; Ribosomes; Risk; Role; Signal Pathway; Signaling Molecule; Small Business Innovation Research Grant; Structure; System; Testing; Tetracyclines; Translational Research; alcohol research; alcohol testing; base; cerebral atrophy; chemical conjugate; drinking; efficacy testing; follow-up; improved; innovation; insight; intraperitoneal; macrophage; monocyte; novel; public health relevance; research study

DESCRIPTION (provided by applicant): The desire to frequently drink large quantities of alcohol is a hallmark of alcoholism. Numerous studies have observed a significant correlation between life-long quantity of alcohol consumed and detriment to the body, including the degree of brain atrophy and risk for alcoholism. Thus, control of high alcohol drinking is an important problem that requires greater understanding at all scientific levels. This application explores new ways to increase our understanding of what controls high alcohol drinking. Preliminary data indicates that the anti-inflammatory antibiotic minocycline (50 mg/kg) is effective in reducing alcohol consumption in adult C57BL/6J (B6) mice when tested in two established drinking paradigms. However, it was not effective in adolescent B6 mice. This has led to our overarching hypothesis that neuroimmune cells and pathways have a significant role in mediating high alcohol drinking. We have devised 2 aims to test our hypothesis. Specific Aim 1 will test the hypothesis that functional microglia play a role in supporting high alcohol consumption. Specific Aim 2 is translational in nature and will test the hypothesis that the diminution of drinking effec of tetracyclines represents a unique activity based on specific structural features of the molecule. Our first aim will explore the requirement for brain microglial in mediating high alcohol drinking using an established animal model, the B6 mouse. These experiments will provide new information on the role of microglia in the brain under presumably non-injurious levels and durations of high alcohol intake. The results will impact not only alcohol research, but the study of reward mechanisms and glial biology. If, as we expect, these studies demonstrate the significance of brain microglia in alcohol consumption, they will potentially change the dogma regarding mechanisms that underlie a high alcohol drinking phenotype. Commensurate with the need for a greater understanding of what controls high alcohol drinking, medications that mitigate the desire to drink large quantities of alcohol are also needed. The second aim will explore the anti-drinking properties of other doses and dosing regimens of minocycline, as well as the efficacy of structurally-modified tetracyclines in our drinking-in-the-dark (DID) paradigm. As the first to test the efficacy of tetracyclines for the reduction of alcohol consumption, the follow-up studies proposed are exploratory and should lead to information that is mechanistic in nature, directly translational and important for the development of better medications. Overall, enthusiasm for the proposal was fairly high.

描述（由申请人提供）：频繁饮酒的欲望是酗酒的标志。许多研究发现，终生饮酒量与对身体的损害（包括脑萎缩程度和酗酒风险）之间存在显着相关性。因此，控制大量饮酒是一个重要问题，需要在所有科学层面上有更多的了解。该应用程序探索了新的 增加我们对控制高度饮酒的了解的方法。初步数据表明，在两种既定饮酒模式中进行测试时，抗炎抗生素米诺环素 (50 mg/kg) 可有效减少成年 C57BL/6J (B6) 小鼠的饮酒量。然而，它对青春期 B6 小鼠无效。这导致了我们的总体假设，即神经免疫细胞和通路在调节高度饮酒中发挥着重要作用。我们设计了 2 个目标来检验我们的假设。具体目标 1 将检验功能性小胶质细胞在支持高饮酒量中发挥作用的假设。具体目标 2 本质上是转化性的，将检验以下假设：四环素的饮酒效应减弱代表了基于分子特定结构特征的独特活性。我们的首要目标是探索大脑小胶质细胞在调节高度酒精中的需求 使用已建立的动物模型 B6 小鼠饮酒。这些实验将提供关于小胶质细胞在可能无害的水平和高酒精摄入持续时间下在大脑中的作用的新信息。研究结果不仅会影响酒精研究，还会影响奖励机制和神经胶质生物学的研究。如果正如我们所期望的那样，这些研究证明了大脑小胶质细胞在饮酒中的重要性，那么它们将有可能改变关于高酒精饮酒表型背后机制的教条。与更好地了解如何控制大量饮酒的需要相称，还需要减轻大量饮酒欲望的药物。第二个目标将探讨米诺环素其他剂量和给药方案的抗饮酒特性，以及结构修饰的四环素在我们的黑暗饮酒（DID）范例中的功效。作为第一个测试四环素类药物减少饮酒量的功效的项目，所提出的后续研究是探索性的，应该会产生本质上是机械性的、直接转化的信息，并且对于开发更好的药物非常重要。 总体而言，对该提案的热情相当高。