Testing a new strategy to reduce alcohol consumption by pH

测试通过 pH 值减少酒精消耗的新策略

• 批准号: 10491351
• 负责人: INYEONG CHOI
• 金额: $ 22.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491351
• 关键词: Abdominal Pain; Acids; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Anion Gap; Astrocytes; Attenuated; Bicarbonates; Biological Factors; Blood; Brain; Cell membrane; Centers for Disease Control and Prevention (U.S.); Cerebrospinal Fluid; Cessation of life; Chronic; Complex; Consumption; DSM-IV; Development; Diagnosis; Diet; Down-Regulation; Fasting; Feeding Methods; Foundations; Frequencies; Goals; Grant; Habits; Human; Hyperglycemia; Individual; Industry; Intervention; Ion Channel; Knockout Mice; Lead; Measures; Mediating; Membrane; Mental disorders; Metabolic; Metabolic acidosis; Motivation; Movement; Mus; National Institute on Alcohol Abuse and Alcoholism; Nausea and Vomiting; Nervous system structure; Neuroglia; Neurons; Neurotransmitter Receptor; Nucleus Accumbens; Pattern; Persons; Pharmaceutical Preparations; Prevention strategy; Procedures; Property; Proteins; Regulation; Relapse; Reporting; Research; Research Personnel; Rewards; Risk; Role; Sedation procedure; Severities; Structure; Surveys; Synapses; Synaptic Cleft; Synaptic Transmission; Testing; Ventral Tegmental Area; World Health Organization; addiction; alcohol abuse therapy; alcohol reward; alcohol use disorder; base; binge drinker; clinically relevant; drinking; feeding; mesolimbic system; mouse model; novel strategies; overexpression; problem drinker; psychologic; restoration; risk minimization; sobriety

Summary pH is an important biological factor in the nervous system, where it alters the structure and activity of numerous proteins including neurotransmitter receptors, ion channels, and synaptic transmission machinery. It may affect neuronal activities in the circuits responsible for alcohol reward value or alcohol modulatory properties, thereby changing alcohol consumption. This project explores the possibility of reducing alcohol consumption by changing brain pH. We recently reported that knockout mice lacking the pH-regulating transporter NBCn1 fail to maintain normal pH in neurons, causing decreased intracellular pH and decreased cerebrospinal fluid pH. Interestingly, these mice drink more alcohol and develop an increase in the reward value of alcohol. Furthermore, NBCn1 is downregulated in mice chronically fed with alcohol and humans with alcohol use disorder (AUD). Thus, abnormal function in NBCn1 not only influences alcohol consumption, but is also induced by alcohol consumption. The central hypothesis based on our previous and preliminary studies is that alcohol causes NBCn1 downregulation and this downregulation reduces brain pH and subsequently increases alcohol consumption. The goal of the project is to obtain more information on the role of NBCn1-mediated pH regulation in alcohol consumption and to provide a foundation for development of pH-dependent strategies to reduce consumption. Achieving this goal will be important for understanding propensity toward alcoholic ketoacidosis (AKA) and developing a prevention strategy. AKA is a metabolic acidosis induced after binge or chronic alcohol abuse followed by fasting. It is characterized by hyperketonemia and high anion gap metabolic acidosis without significant hyperglycemia, and causes nausea, vomiting, and abdominal pain. Two specific aims are set to achieve the goal. Aim 1 will examine the effects of pH restoration on increased alcohol consumption in NBCn1 knockout mice. The efficacy of pH in reducing alcohol consumption and NBCn1 involvement in this pH effect will be investigated. A mechanistic approach will then be used by injecting NBCn1 to the mouse brain, primarily in the mesolimbic system. Aim 2 will examine the effects of pH on AKA in mice. We developed a mouse model of AKA using a clinically relevant alcohol feeding procedure. We will test whether adjusting systemic pH attenuates AKA and whether NBCn1 is involved. Bicarbonate will be added to the diet and AKA induction and severity will be measured. We will also examine NBCn1 expression and activity during AKA development. In addition, the effects of NBCn1 overexpression in the mesolimbic system will be assessed. The results will provide unprecedented information about the pH effects on alcohol consumption and NBCn1 involvement in producing these effects. We anticipate that the project will lead to the establishment of a new research platform for pH-dependent strategies to reduce alcohol consumption for ordinary drinkers who want to drink less, and chronic or binge drinkers who could be metabolically complicated with AKA.

概括 pH 值是神经系统中一个重要的生物因素，它改变了许多神经系统的结构和活性。 蛋白质，包括神经递质受体、离子通道和突触传递机制。它可能会影响 负责酒精奖励值或酒精调节特性的回路中的神经元活动，从而 改变饮酒量。该项目探讨了通过以下方式减少酒精消费的可能性： 改变大脑的pH值。我们最近报道，缺乏 pH 调节转运蛋白 NBCn1 的基因敲除小鼠失败了 维持神经元正常的pH值，导致细胞内pH值降低和脑脊液pH值降低。 有趣的是，这些小鼠喝了更多的酒，并且酒精的奖励值也增加了。 此外，NBCn1 在长期饮酒的小鼠和饮酒的人类中表达下调 紊乱（澳元）。因此，NBCn1的功能异常不仅影响饮酒，而且还影响饮酒。 由饮酒引起。基于我们之前和初步研究的中心假设是 酒精会导致 NBCn1 下调，这种下调会降低大脑 pH 值并随后升高 饮酒量。该项目的目标是获得有关 NBCn1 介导的 pH 作用的更多信息 调节酒精消费，并为开发依赖 pH 值的策略奠定基础 减少消耗。实现这一目标对于了解酗酒倾向非常重要 酮症酸中毒（AKA）并制定预防策略。 AKA 是暴饮暴食或暴饮暴食后引起的代谢性酸中毒 长期酗酒，然后禁食。其特点是高酮血症和高阴离子间隙代谢 没有明显高血糖的酸中毒，并引起恶心、呕吐和腹痛。两个具体 设定目标是为了实现目标。目标 1 将检查 pH 值恢复对酒精含量增加的影响 NBCn1 敲除小鼠的消耗。 pH 值在减少酒精消耗和 NBCn1 方面的功效 将研究这种 pH 效应的参与。然后将通过注射 NBCn1 使用机械方法 到小鼠大脑，主要是在中脑边缘系统。目标 2 将检查 pH 对小鼠 AKA 的影响。 我们使用临床相关的酒精喂养程序开发了 AKA 小鼠模型。我们将测试 调节全身 pH 值是否会减弱 AKA 以及 NBCn1 是否参与其中。将添加碳酸氢盐 将测量饮食和 AKA 诱导和严重程度。我们还将检查 NBCn1 表达和活性 在 AKA 开发期间。此外，NBCn1在中脑边缘系统中过度表达的影响将是 评估。研究结果将提供有关 pH 值对酒精消耗和影响的前所未有的信息。 NBCn1 参与产生这些效应。我们预计该项目将导致建立一个 新的 pH 依赖策略研究平台可减少普通饮酒者的饮酒量 想要少喝酒的人，以及可能患有 AKA 代谢复杂性的慢性或酗酒者。