Reversal of nucleus accumbens LTD in ethanol dependent mice

乙醇依赖小鼠伏隔核LTD的逆转

• 批准号: 8003827
• 负责人: Zachary Marvin Jeanes
• 金额: $ 3.25万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 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/8003827
• 关键词: Abstinence; Affect; Alcohol dependence; Alcoholism; Area; Brain; Cause of Death; Chemosensitization; Chronic; Development; Dopamine Receptor; Drug Addiction; Drug abuse; Drug usage; Ethanol; Ethanol dependence; Exhibits; Future; Healthcare; Mental Depression; Mus; Neurobiology; Neurons; Nucleus Accumbens; Persons; Pharmaceutical Preparations; Play; Process; Research; Rewards; Role; Site; Societies; Stimulus; Structure; Symptoms; Synapses; Synaptic plasticity; Transgenic Mice; Withdrawal; alcohol exposure; alcohol use disorder; alcoholism therapy; base; cost; drug of abuse; drug seeking behavior; effective therapy; in vivo; insight; mesolimbic system; neural circuit; neural information processing; novel; problem drinker; public health relevance; research study; response; synaptic depression

DESCRIPTION (provided by applicant): Ethanol dependence is a widespread affliction with annual cost to society in the hundreds of billions of dollars. Drug dependence is generally regarded as the inability to abstain from drug use despite the known negative consequences and is often accompanied by symptoms of physical withdrawal during protracted periods of abstinence. Chronic drug abuse has been shown to induce neurobiological changes that are thought to underlie the progression to compulsive drug seeking behaviors. Current research in ethanol dependence largely focuses upon the mesolimbic dopamine system, of which, the nucleus accumbens (NAc) plays a central role in the processing of neural information related to rewarding stimuli. In order to effectively treat ethanol dependence, it is vital to determine which specific changes in neural circuit function contribute to the shift from a normal to an ethanol dependent state. One mechanism through which neurons can reorganize themselves in response to different stimuli is called synaptic plasticity. Plasticity mechanisms are thought to participate in the rewiring of neural circuits in response to drugs of abuse. Our understanding of the synaptic and intracellular processes controlling plasticity of the principle neurons, called medium spiny neurons (MSNs), of such an important brain structure is lacking. This proposal builds on preliminary studies that indicate MSNs from the NAc exhibit a reversal of synaptic plasticity following in vivo chronic intermittent ethanol exposure. This finding is significant because this switch in synaptic plasticity from depression to potentiation is a direct example of the rewiring of normal cellular activity thought to occur in the drug-dependent brain. The overarching hypothesis of this proposal is that neuroadaptive alterations in excitatory synaptic plasticity in the NAc contribute to the expression of ethanol dependence. The first part of this proposal is structured to elucidate the mechanisms underlying the conversion from synaptic depression to potentiation. MSNs are commonly separated into two subpopulations based on their expression of specific dopamine receptor subtypes, which project to different brain structures. The second half of this proposal will use transgenic mouse lines to investigate the propensity of these two subpopulations of MSNs to exhibit differing forms of synaptic plasticity before and after ethanol exposure. These experiments will be the first to investigate the ethanol modulation of synaptic plasticity in the NAc. The results should provide new insights that will help to identify novel sites for future development of pharmacologic agents for the treatment of alcoholism. PUBLIC HEALTH RELEVANCE: Alcoholism and complications from alcohol dependence make up the fourth leading cause of death in the U.S., and the resulting health care-related expenses are estimated at nearly $200 billion annually. This proposal contributes to ongoing research aimed at discovering what changes occur in the brain as a person becomes an alcoholic. Research in this area is vital to uncover new and effective treatments to help those affected with alcohol-use disorders recover and contribute positively to society.

描述（由申请人提供）：乙醇依赖是一种普遍存在的疾病，每年给社会造成数千亿美元的损失。药物依赖通常被认为是尽管药物有已知的负面后果但仍无法戒除药物使用，并且在长期戒断期间常常伴有身体戒断症状。慢性药物滥用已被证明会引起神经生物学变化，这些变化被认为是发展为强迫性药物寻求行为的基础。 目前对乙醇依赖的研究主要集中在中脑边缘多巴胺系统，其中伏隔核（NAc）在处理与奖励刺激相关的神经信息中发挥着核心作用。为了有效治疗乙醇依赖，确定神经回路功能的哪些具体变化有助于从正常状态转变为乙醇依赖状态至关重要。 神经元可以自我重组以响应不同刺激的一种机制称为突触可塑性。人们认为可塑性机制参与了神经回路对滥用药物的反应的重新布线。我们对控制如此重要的大脑结构的主要神经元（称为中棘神经元（MSN））可塑性的突触和细胞内过程缺乏了解。该提议建立在初步研究的基础上，初步研究表明，在体内慢性间歇性乙醇暴露后，来自 NAc 的 MSN 表现出突触可塑性的逆转。这一发现意义重大，因为突触可塑性从抑制到增强的转变是药物依赖性大脑中正常细胞活动重新布线的直接例子。 该提议的总体假设是 NAc 中兴奋性突触可塑性的神经适应性改变有助于乙醇依赖性的表达。该提案的第一部分旨在阐明从突触抑制到增强的转化机制。 MSN 通常根据其特定多巴胺受体亚型的表达分为两个亚群，这些亚型投射到不同的大脑结构。该提案的后半部分将使用转基因小鼠品系来研究这两个 MSN 亚群在乙醇暴露前后表现出不同形式的突触可塑性的倾向。 这些实验将首次研究 NAc 中突触可塑性的乙醇调节。这些结果应该提供新的见解，有助于确定未来开发治疗酒精中毒的药物的新位点。 公共卫生相关性：酗酒和酒精依赖并发症是美国第四大死因，由此产生的医疗保健相关费用每年估计近 2000 亿美元。该提案有助于正在进行的研究，旨在发现当一个人成为酗酒者时大脑会发生什么变化。该领域的研究对于发现新的有效治疗方法至关重要，以帮助酒精使用障碍患者康复并为社会做出积极贡献。