The Role of BK Channel Composition in Alcohol Tolerance and Consumption

BK 通道组成在酒精耐受性和消费中的作用

• 批准号: 7690954
• 负责人: STEVEN N TREISTMAN
• 金额: $ 31.88万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7690954
• 关键词: Action Potentials; Acute; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Animal Model; Behavior; Behavioral; Biological Assay; Brain; Cells; Chronic; Consumption; Corpus striatum structure; Culture Media; Data; Development; Drug Addiction; Drug Tolerance; Drug effect disorder; Ethanol; Excision; Exposure to; Future; Genetically Engineered Mouse; Goals; Habits; Hour; Human; Imaging Techniques; Knock-out; Measures; Mediator of activation protein; Modification; Molecular; Molecular Biology; Mus; Neurons; Outcome; Pharmaceutical Preparations; Phosphotransferases; Potassium Channel; Property; Protein Subunits; Protocols documentation; Public Health; Research; Rewards; Role; Signal Pathway; Slice; Structure; System; Techniques; Testing; Time; Variant; Water; Work; addiction; alcohol exposure; alcohol response; alcohol reward; base; behavior test; behavioral tolerance; drinking; drug metabolism; drug of abuse; drug reward; drug withdrawal; follow-up; large-conductance calcium-activated potassium channels; preference; public health relevance; research study

DESCRIPTION (provided by applicant): Behavioral tolerance is a hallmark of exposure to most drugs of abuse. It is characterized by reduced drug effects over time, either via altered metabolism of the drug, or functionally, whereby the effects of the drug decrease in spite of unaltered concentration. Indeed, the presence of enhanced acute behavioral tolerance in humans can serve as a marker for the likelihood of a future development of alcoholism. The large conductance potassium ion channel (BK) has become increasingly recognized as an important target of alcohol action, both in the intoxicating actions of the drug, as well as in adaptation to the drug (tolerance). This proposal is based upon exciting new data which identifies the BK channel beta4 subunit as an important mediator of alcohol tolerance and consumption, and provides an animal model to examine the relationship between molecular and behavioral tolerance, and consumption. We will make use of genetically engineered mice, in which the beta4 subunit is either present or "knocked out". In Aim 1, we test the hypothesis that BK beta4 influences acute tolerance via a mechanism involving kinases and associated signaling pathways. Electrophysiological experiments will probe the role of kinases in BK acute tolerance in expression systems and in neurons of the striatum, which is important in drug reward and addiction. In Aim 2, we test the hypothesis (based upon preliminary data) that beta4's influence on rapid tolerance will not be as pronounced as in acute tolerance. These studies will utilize electrophysiological, molecular biology, and imaging techniques, and will probe at the molecular, cellular, and behavioral levels. Aim 2 will include studies on the role of beta4 in the finding, described in our preliminary data that in striatal neurons, there is a "switch" which is activated after 3 to 6 hrs of alcohol exposure, which radically changes the duration of tolerance after alcohol withdrawal. This has implications for the development of alcohol dependency as a function of drinking habits. Finally, in Aim 3, we test the hypothesis that beta4's influence on alcohol consumption will reflect influences on behavioral parameters such as alcohol preference and reward, both known to influence consumption. A two bottle choice variant of the "drinking in the dark" (DID) paradigm will be utilized to measure ethanol vs. water preference in beta4 KO and WT mice. In addition, we will measure the rewarding properties of ethanol in WT and beta4 KO mice using a conditioned place preference (CPP) assay. Together, these experiments will help identify the role of the beta4 subunit and acute tolerance in motivational behaviors underlying alcohol consumption. PUBLIC HEALTH RELEVANCE: Alcoholism represents one of the most important problems in the public health arena. Tolerance, which develops with alcohol use, may be related to the development of drug dependency and addiction. In this proposal, we pursue exciting new data which indicates a role for the BK channel beta4 subunit protein in the control of alcohol tolerance and consumption.

描述（由申请人提供）：行为耐受性是接触大多数滥用药物的标志。其特征是随着时间的推移药物作用减弱，或者通过药物代谢的改变，或者在功能上，尽管浓度不变，但药物的作用减弱。事实上，人类急性行为耐受性的增强可以作为未来酗酒可能性的一个标志。大电导钾离子通道（BK）已越来越被认为是酒精作用的重要靶点，无论是在药物的中毒作用还是在对药物的适应（耐受性）方面。该提议基于令人兴奋的新数据，该数据确定了 BK 通道 beta4 亚基是酒精耐受性和消费的重要介质，并提供了一个动物模型来检查分子和行为耐受性与消费之间的关系。我们将利用基因工程小鼠，其中β4亚基要么存在，要么“被敲除”。在目标 1 中，我们测试了这样的假设：BK beta4 通过涉及激酶和相关信号通路的机制影响急性耐受性。电生理学实验将探讨激酶在表达系统和纹状体神经元中 BK 急性耐受中的作用，这对于药物奖励和成瘾很重要。在目标 2 中，我们测试了以下假设（基于初步数据）：β4 对快速耐受的影响不会像急性耐受中那样明显。这些研究将利用电生理学、分子生物学和成像技术，并在分子、细胞和行为水平上进行探索。目标 2 将包括对 β4 在这一发现中的作用的研究，我们的初步数据中描述的是，在纹状体神经元中，有一个“开关”，在酒精暴露 3 至 6 小时后被激活，这从根本上改变了酒精耐受的持续时间。酒精戒断。这对于作为饮酒习惯函数的酒精依赖的发展具有影响。最后，在目标 3 中，我们测试了这样的假设：β4 对酒精消费的影响将反映对行为参数的影响，例如酒精偏好和奖励，这两者都已知会影响消费。 “黑暗中饮酒”(DID) 范例的两瓶选择变体将用于测量 beta4 KO 和 WT 小鼠对乙醇与水的偏好。此外，我们将使用条件位置偏好（CPP）测定来测量乙醇对 WT 和 beta4 KO 小鼠的奖励特性。总之，这些实验将有助于确定 β4 亚基和急性耐受性在饮酒动机行为中的作用。 公共卫生相关性：酗酒是公共卫生领域最重要的问题之一。随着饮酒而产生的耐受性可能与药物依赖和成瘾的发展有关。在本提案中，我们追求令人兴奋的新数据，这些数据表明 BK 通道 beta4 亚基蛋白在控制酒精耐受性和消费方面的作用。