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: 10303628
• 负责人: INYEONG CHOI
• 金额: $ 18.54万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303628
• 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; 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.

摘要 PH值是神经系统中一个重要的生物因素，在神经系统中，它改变了许多 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 负责酒精奖赏价值或酒精调节特性的回路中的神经元活动，从而 改变酒精消费。该项目探讨了通过以下方式减少酒精消费的可能性 改变大脑的酸碱度。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 维持神经元正常pH，导致细胞内pH降低，脑脊液pH降低。 有趣的是，这些小鼠喝的酒更多，酒精的奖赏价值也会增加。 此外，在长期饮酒的小鼠和饮酒的人类中，NBCn1的表达下调 精神障碍(澳元)。因此，NBCn1的功能异常不仅影响饮酒，而且还 由饮酒引起的。基于我们之前和初步研究的中心假设是 酒精引起NBCn1的下调，这种下调降低了大脑的pH值，随后又增加了 饮酒。该项目的目标是获得更多关于NBCn1介导的pH的作用的信息 对酒精消费的监管，并为制定依赖pH的战略提供基础，以 减少消费。实现这一目标对于了解酗酒倾向是很重要的 酮症酸中毒(AKA)和制定预防战略。AKA是暴饮暴食后引起的代谢性酸中毒 长期酗酒后禁食。它的特点是高酮血症和高阴离子间隙代谢。 无明显高血糖的酸中毒，引起恶心、呕吐和腹痛。两个具体的 目标是为实现目标而设定的。目标1将检查pH恢复对酒精增加的影响 在NBCn1基因敲除小鼠中的消费。PH值对减少饮酒量和NBCn1的影响 我们将对这种pH效应的影响进行调查。然后将通过注入NBCn1来使用机械方法 对小鼠的大脑，主要是在中脑边缘系统。目的2将研究pH对小鼠AKA的影响。 我们开发了一种使用临床相关酒精喂养程序的AKA小鼠模型。我们将测试 调节全身pH是否减弱AKA以及NBCn1是否参与其中。小苏打将被加入到 将测量饮食和AKA的诱因和严重程度。我们还将检测NBCn1的表达和活性 在AKA开发期间。此外，NBCn1在中边缘系统的过度表达的影响将是 评估过了。这一结果将提供有关酸碱度对酒精消费影响的前所未有的信息 NBCn1参与了这些效应的产生。我们预计，该项目将导致建立一个 PH依赖策略的新研究平台，以减少普通饮酒者的酒精消耗量 想要少喝酒，以及长期或酗酒的人，他们可能会在代谢上合并AKA。