Neuroimmune Interactions in High Alcohol Drinking

描述（由申请人提供）：经常大量饮酒的欲望是酒精中毒的标志。许多研究已经观察到终生饮酒量与身体损害之间的显著相关性，包括脑萎缩的程度和酗酒的风险。因此，控制酗酒是一个重要的问题，需要在所有科学层面上更好地理解。该应用程序探索了新的 增加我们对控制高酒精饮酒的理解的方法。初步数据表明，当在两种已建立的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C57 BL/6 J（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介导高酒精饮用中起着重要作用。我们设计了两个目标来验证我们的假设。具体目标1将测试功能性小胶质细胞在支持高酒精消费中发挥作用的假设。特定目的2本质上是翻译性的，将检验四环素类药物的饮水效应减弱代表基于分子特定结构特征的独特活性的假设。我们的第一个目标是探索大脑小胶质细胞介导高酒精的需求 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大脑中的作用的新信息，这些作用可能是在高酒精摄入量的非伤害性水平和持续时间下。这些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。如果像我们预期的那样，这些研究证明了大脑小胶质细胞在饮酒中的重要性，那么它们将可能改变关于高度饮酒表型机制的教条。为了更好地了解是什么控制了大量饮酒，也需要减轻大量饮酒欲望的药物。第二个目标将探索其他剂量和二甲胺四环素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中饮酒（DID）范例中的功效。作为第一个测试四环素类药物减少饮酒的疗效的后续研究，建议是探索性的，并应导致信息，是机械性质，直接转化和更好的药物开发的重要。 总体而言，对该提案的热情相当高。

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.