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: 8142821
• 负责人: Zachary Marvin Jeanes
• 金额: $ 3.11万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8142821
• 关键词: Abstinence; Address; Affect; Alcohol consumption; Alcohol dependence; Alcoholism; Area; Brain; Cause of Death; Cells; Chemosensitization; Chronic; Corpus striatum structure; Development; Dopamine D1 Receptor; Dopamine Receptor; Dorsal; Drug Addiction; Drug abuse; Drug usage; Equilibrium; Ethanol; Ethanol dependence; Exhibits; Exposure to; Future; Glutamates; Healthcare; In Vitro; Label; Lead; Long-Term Depression; Long-Term Potentiation; Mediator of activation protein; Mental Depression; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurobiology; Neurons; Nucleus Accumbens; Persons; Pharmaceutical Preparations; Play; Population; Prefrontal Cortex; Process; Reporting; Research; Rewards; Role; Site; Societies; Stimulus; Structure; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; System; Time; Transgenic Mice; Ventral Tegmental Area; Withdrawal; Work; abstracting; alcohol exposure; alcohol use disorder; alcoholism therapy; base; conditioning; cost; drug of abuse; drug seeking behavior; effective therapy; in vivo; insight; mesolimbic system; neural circuit; neural information processing; novel; patch clamp; problem drinker; receptor; research study; response; reward processing; synaptic depression; vapor

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.

描述（由申请人提供）：乙醇依赖是一种普遍的痛苦，每年给社会带来数千亿美元的损失。药物依赖通常被认为是尽管已知会产生不良后果但仍无法戒断药物使用，而且在长期戒断期间往往伴有身体戒断症状。慢性药物滥用已被证明会诱导神经生物学变化，这些变化被认为是强迫性药物寻求行为进展的基础。 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，丘脑核（NAc）在与奖励刺激相关的神经信息加工中起着核心作用。为了有效地治疗乙醇依赖，确定神经回路功能的哪些特定变化有助于从正常状态转变为乙醇依赖状态是至关重要的。 神经元可以通过一种机制来重组自己以响应不同的刺激，这种机制被称为突触可塑性。可塑性机制被认为参与了神经回路的重新布线，以响应滥用药物。我们对控制这种重要大脑结构的主要神经元（称为中型棘神经元（MSN））可塑性的突触和细胞内过程的理解是缺乏的。该建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，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正常细胞活动重新布线的直接例子，被认为发生在药物依赖性大脑中。 这个建议的首要假设是，神经适应性改变兴奋性突触可塑性的NAc有助于表达乙醇依赖性。本建议的第一部分是结构化的，以阐明从突触抑制到增强转换的机制。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。本提案的后半部分将使用转基因小鼠系来研究这两个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。 这些实验将是第一个研究乙醇调制的突触可塑性的NAc。这些结果应该提供新的见解，这将有助于确定新的网站，为未来发展的药物治疗酒精中毒。