Role of Rostromedial Tegmental Nucleus in alcohol addiction

鼻内侧被盖核在酒精成瘾中的作用

• 批准号: 8997041
• 负责人: JIANG-HONG YE
• 金额: $ 33.52万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-03 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8997041
• 关键词: Acute; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Area; Attenuated; Automobile Driving; Behavior; Behavioral; Brain; Cause of Death; Cell Nucleus; Data; Development; Disinhibition; Dopaminergic Cell; Electrophysiology (science); Ethanol; Ethanol dependence; Goals; Health; Heavy Drinking; Immunohistochemistry; Infusion procedures; Knowledge; Laboratories; Light; Literature; Measures; Methods; Microinjections; Molecular Genetics; Morphine; Mus; Naltrexone; Narcotic Antagonists; Neurons; Opioid; Opioid Receptor; Pharmacology; Pharmacotherapy; Play; Prevention strategy; Property; Protocols documentation; Rattus; Regulation; Research; Rewards; Rodent; Role; Slice; Structure; Synapses; Synaptic Transmission; Techniques; Testing; United States; Ventral Tegmental Area; Viral; Work; alcohol effect; alcoholism therapy; base; cellular targeting; dopaminergic neuron; drinking behavior; drug of abuse; gamma-Aminobutyric Acid; immunoreactivity; improved; innovation; insight; naloxonazine; neural circuit; neurobiological mechanism; neuronal circuitry; novel; optogenetics; research study; transmission process; treatment strategy

DESCRIPTION (provided by applicant): The neurobiological mechanisms underlying the addictive property of ethanol remain obscure. It is generally accepted that the addictive property of ethanol is associated with its ability to increase the activity of dopaminergic neurons in the ventral tegmental area (VTA) in the brain. These neurons are under the powerful control of synaptic inputs. Thus, the synaptic regulation of dopaminergic neurons is a key initial step in reward mechanisms leading to alcohol addiction. The majority of the afferents to dopaminergic neurons are GABAergic and usually inhibitory. Some drugs of abuse, such as opioids, stimulate VTA-dopaminergic neurons through suppression of GABAergic transmission - that is by disinhibition. Emerging evidence indicates that the rostromedial tegmental nucleus (RMTg), a newly defined structure with dense ¿-opioid receptor immunoreactivity, is a major GABAergic afferent to dopaminergic neurons, and a key structure in ¿-opioid receptor-dependent regulation of dopaminergic neurons. However, the functional mechanisms connecting the RMTg inputs to the dopaminergic neurons with alcohol drinking behavior remain obscure. Our long term goal is to understand the neurobiological mechanisms underlying alcohol addiction. The objective in this application is to define RMTg's role in ethanol drinking behavior by identifying its contribution to ethanol-induced activation of VTA dopaminergic neurons and determining the influence of RMTg neuronal activity on ethanol intake. Our proposed experiments will specifically test the central hypothesis that the RMTg projection to VTA dopaminergic cells plays a key role in the control of regulating ethanol drinking behavior by strongly regulating ethanol-induced enhancement of VTA-dopaminergic neuron activity. This central hypothesis will be tested in two separate but integrated Aims. Aim 1 will combine ex vivo electrophysiology, tract tracing experiments, targeted neuronal activation/inactivation, molecular genetics and optogenetic techniques to functionally dissect a neuronal circuit important for acute ethanol's action on dopaminergic neurons. Aim 2 will determine the effect of altering RMTg activity on ethanol intake. To test the hypothesis that the RMTg plays a key role in ethanol drinking, we will manipulate RMTg function by intra-RMTg infusion of relevant pharmacological agents and then study consequent changes in ethanol intake, using the intermittent 2-bottle choice paradigm. The studies are significant because they will advance our knowledge of the neural circuitries that determine excessive alcohol consumption. The proposed studies are innovative, because they will characterize a previously understudied effect of ethanol on the RMTg neurons, and its subsequent indirect effect on VTA-dopaminergic neurons, as well as the role of ¿-opioid receptors in the RMTg in drinking behavior. The results of this project will provide valuable information on novel mechanisms underlying the addictive properties of alcohol and should identify novel cellular targets for the development of improved treatment of alcoholism.

描述（由适用提供）：乙醇添加特性的基础的神经生物学机制仍然晦涩难懂。人们普遍认为，乙醇的额外特性与它增加大脑腹侧盖区域（VTA）中多巴胺能神经元活性的能力有关。这些神经元受到合成输入的强大控制。这，多巴胺能神经元的合成调节是导致添加酒精的奖励机制的关键第一步。多巴胺能神经元的大多数传入都是GABA能，通常是抑制性的。一些滥用药物（例如阿片类药物）通过抑制GABA能传播刺激VTA多巴巴胺能神经元 - 这是通过抑制作用。新兴证据表明，叶状性技术核us（RMTG）是一种新定义的结构，具有致密的 - 阿片受体免疫反应性，是对多巴胺能神经元的主要GABA能情感，并且是®-阿片接收者的关键结构 - 依赖于阿片类药物的多发性神经剂的调节。但是，将RMTG输入与饮酒行为连接到多巴胺能神经元的功能机制仍然晦涩难懂。我们的长期目标是了解酒精成瘾的神经生物学机制。本应用的目的是通过确定其对乙醇诱导的VTA多巴胺能神经元激活的贡献，并确定RMTG神经元活性对乙醇摄入的影响，从而定义RMTG在乙醇饮用行为中的作用。我们提出的实验将特别检验中心假设，即对VTA多巴胺能细胞的RMTG投影通过强烈调节乙醇诱导的VTA-多巴胺能神经元活性的增强来控制调节乙醇饮用行为。该中心假设将以两个单独但综合的目的进行检验。 AIM 1将结合离体电生理学，道追踪实验，靶向神经元激活/灭活，分子遗传学和光遗传学技术，以功能地剖析对急性乙醇对多巴胺能神经元作用重要的神经元电路。 AIM 2将确定改变RMTG活性对乙醇摄入的影响。为了检验RMTG在乙醇饮用中起关键作用的假设，我们将通过Intra-RMTG输注相关的药理学剂来操纵RMTG功能，然后使用间歇性的2瓶装选择范式研究随之而来的乙醇摄入量的变化。这些研究之所以重要，是因为它们将提高我们对确定过量饮酒的神经元电路的了解。拟议的研究具有创新性，因为它们将表征乙醇对乙醇对RMTG神经元的作用，以及其随后对VTA-多巴胺能神经元的间接作用，以及 - 阿片受体在RMTG在饮酒行为中的作用。该项目的结果将提供有关酒精添加特性的新机制的宝贵信息，并应确定新的细胞靶标，以开发改善酒精中毒的治疗方法。