Role of NR2B Subunit in Glutamate Signaling and Anxiety during Ethanol Withdrawal

NR2B 亚基在乙醇戒断期间谷氨酸信号传导和焦虑中的作用

• 批准号: 8001152
• 负责人: Tiffany A Wills
• 金额: $ 4.76万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8001152
• 关键词: Acute; Affect; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholism; Amygdaloid structure; Anxiety; Area; Behavior; Brain; Cell Nucleus; Chronic; Complex; Complication; Dependence; Development; Disease; Dose; Ethanol; Ethanol dependence; Glutamates; Knock-out; N-Methyl-D-Aspartate Receptors; Negative Reinforcements; Neurotransmitters; Pharmaceutical Preparations; Pharmacology; Positive Reinforcements; Production; Relapse; Reliance; Role; Signal Transduction; Stimulus; Stress; Structure of terminal stria nuclei of preoptic region; System; Viral; Withdrawal; Work; alcohol abstinence; alcohol effect; alcohol exposure; alcoholism therapy; disorder later incidence prevention; novel; public health relevance; receptor function; response; transmission process

DESCRIPTION (provided by applicant): Alcoholism is known to be a chronic relapsing disorder. As alcohol use transitions to dependence, there is a shift in the motivational drive from being initially influenced by positive reinforcement (pleasurable effects from ethanol) to later reliance on negative reinforcement (withdrawal/negative affect from ethanol). One behavior that modulates relapse in dependent subjects during withdrawal is anxiety. Therefore, understanding the mechanisms that contribute to anxiety during withdrawal is critically important to the treatment of alcoholism. A region that is particularly involved in the modulation of anxiety and stress is the extended amygdala (bed nucleus of the stria terminalis; BNST and central nucleus of the amygdala; CeA).These nuclei have been shown to modulate responses to anxiogenic stimuli and stress- induced relapse to drug taking and, therefore, critical to the understanding of ethanol dependence. One neurotransmitter system present in the extended amygdala that is particularly susceptible to the effects of ethanol is glutamate. Multiple lines of evidence have illustrated that acute ethanol administration at pharmacologically relevant doses selectively inhibits glutamate transmission through the NMDA receptor (NMDAR). Further, ethanol also seems to be selectivity more sensitive to NMDARs that contain NR2B (also referred to as the GluN2B) subunit. While there is an inhibition of NMDAR function following acute ethanol, more chronic ethanol administrations either enhance or inhibit glutamate transmission depending on the region evaluated. Several studies have demonstrated that these effects of ethanol on NMDARs occur in regions of the extended amygdala (BNST and CeA). In the CeA, acute ethanol inhibited NMDARs, while chronic ethanol treatment enhanced this inhibition. Further, a NR2B antagonist was able to block this ethanol induced inhibition from acute and chronic ethanol treatment. In the BNST, acute ethanol inhibits NMDAR responses and chronic ethanol exposure enhances their function in an NR2B related manner. Since these regions of the extended amygdala are critical for the modulation of anxiety, it is possible the disrupted glutamate transmission in these regions could contribute to the production of ethanol withdrawal-induced anxiety. The major complication in evaluating the specific role of NR2B in ethanol's effects is the complex pharmacology of NMDARs. These problems can be circumvented with the use of both a conditional and viral knock-out (KO) of NR2B. This proposal will evaluate the requirement of NR2B (with conditional and viral KO of NR2B) in the inhibition of NMDAR function following acute ethanol and the enhancement/inhibition of NMDAR function following chronic treatment (Aim 1). Further, this work will assess the role of the NR2B subunit, with conditional and viral KOs, in basal and withdrawal induced anxiety from chronic ethanol exposure (Aim 2). PUBLIC HEALTH RELEVANCE: Understanding of the development of anxiety during alcohol withdrawal is critical to the prevention of relapse during alcohol abstinence and overall treatment of alcoholism. This project investigates the effects of alcohol on a primary neurotransmitter system (glutamate) in key brain areas (the extended amygdala) known to be important for the development of anxiety. This work will provide information necessary for the development of novel treatments for alcoholism.

描述（由申请人提供）：酗酒是一种慢性复发障碍。随着酒精使用过渡到依赖性的转变，动机驱动因素从最初受到积极强化（乙醇的愉悦作用）的影响到后来依赖负面增强的依赖（乙醇的戒断/负面影响）。戒断期间调节依赖受试者复发的一种行为是焦虑。因此，了解在戒断过程中导致焦虑的机制对于酗酒至关重要。特别参与焦虑和压力调节的区域是扩展的杏仁核（杏仁核的床核；杏仁核的BNST和中心核； CEA）。这些核已被证明可以调节对焦虑剂刺激的响应，并对吸毒对吸毒和吸毒的依赖性的依赖性依赖，从而对吸毒的理解，因此对乙醇的了解。扩展的杏仁核中存在的一种神经递质系统特别容易受到乙醇的影响。多种证据表明，在药理学相关剂量下的急性乙醇施用选择性地抑制通过NMDA受体（NMDAR）的谷氨酸传播。此外，乙醇似乎也对包含NR2B（也称为Glun2b）亚基的NMDAR更敏感。尽管急性乙醇后有NMDAR功能的抑制作用，但根据评估的区域，更多的慢性乙醇施用可以增强或抑制谷氨酸的传播。几项研究表明，乙醇对NMDAR的这些影响发生在扩展的杏仁核（BNST和CEA）的区域。在CEA中，急性乙醇抑制了NMDAR，而慢性乙醇治疗增强了这种抑制作用。此外，NR2B拮抗剂能够阻止该乙醇引起的急性和慢性乙醇处理的抑制作用。在BNST中，急性乙醇抑制NMDAR反应，而慢性乙醇暴露以相关的NR2B方式增强其功能。由于扩展的杏仁核的这些区域对于调节焦虑至关重要，因此这些区域中有可能破坏的谷氨酸传播可能有助于产生乙醇戒断引起的焦虑。评估NR2B在乙醇作用中的特定作用的主要并发症是NMDAR的复杂药理学。通过使用NR2B的条件和病毒敲除（KO），可以规避这些问题。该提案将评估NR2B（NR2B的条件和病毒KO）在急性乙醇后抑制NMDAR功能的需求，并在慢性治疗后增强/抑制NMDAR功能（AIM 1）。此外，这项工作将通过条件和病毒KOS在基底和戒断引起的慢性乙醇暴露引起的焦虑中评估NR2B亚基的作用（AIM 2）。 公共卫生相关性：对戒酒过程中焦虑发展的理解对于预防戒酒和酒精中毒的整体治疗过程中的复发至关重要。该项目调查了酒精对主要大脑区域（扩展杏仁核）的原发性神经递质系统（谷氨酸）的影响，这对于焦虑的发展很重要。这项工作将为开发新颖的酒精中毒提供必要的信息。