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: 9210577
• 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/9210577
• 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; 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; alcohol effect; alcoholism therapy; base; cellular targeting; dopaminergic neuron; drinking behavior; drug of abuse; experimental study; gamma-Aminobutyric Acid; immunoreactivity; improved; induced pluripotent stem cell; innovation; insight; naloxonazine; neural circuit; neurobiological mechanism; neuronal circuitry; novel; optogenetics; public health relevance; 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 μ-opioid receptor immunoreactivity, is a major GABAergic afferent to dopaminergic neurons, and a key structure in μ-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 μ-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（由申请人提供）：乙醇成瘾特性的神经生物学机制仍然不清楚。人们普遍认为，乙醇的成瘾特性与其增加腹侧被盖区（VTA）多巴胺能神经元活性的能力有关。这些神经元受到突触输入的强大控制，因此，多巴胺能神经元的突触调节是导致酒精成瘾的奖励机制的关键初始步骤。多巴胺能神经元的传入神经元是 GABA 能神经元，并且通常是抑制性的。一些滥用药物，例如阿片类药物，通过抑制 GABA 能神经元的传递来刺激 VTA 多巴胺能神经元，即通过去抑制作用来刺激 VTA 多巴胺能神经元。具有致密 μ-阿片受体免疫反应性的明确结构，是多巴胺能神经元的主要 GABA 传入神经元，也是关键然而，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不清楚。我们的长期目标是了解酒精成瘾的神经生物学机制。该应用旨在通过确定 RMTg 对乙醇诱导的 VTA 多巴胺能神经元激活的贡献并确定 RMTg 神经元活动对乙醇摄入的影响来定义 RMTg 在乙醇饮酒行为中的作用。实验将具体测试中心假设，即 RMTg 投射到 VTA 多巴胺能细胞，通过调节乙醇诱导的 VTA 多巴胺能神经元活性增强，在控制乙醇饮酒行为方面发挥关键作用。这一中心假设将在两个单独的项目中进行测试。但综合目标 1 将结合离体电生理学、束追踪实验、靶向神经激活/失活、分子遗传学和光遗传学技术，从功能上剖析对急性发作很重要的神经回路。目标 2 将确定改变 RMTg 活性对乙醇摄入的影响 为了检验 RMTg 在乙醇饮用中发挥关键作用的假设，我们将通过在 RMTg 内输注相关药物来操纵 RMTg 功能。然后使用间歇性两瓶选择范式研究乙醇摄入量的后续变化。这些研究意义重大，因为它们将增进我们对决定过量饮酒的神经回路的了解。拟议的研究具有创新性，因为它们将描述先前研究的乙醇对 RMTg 神经元的影响，及其随后对 VTA 多巴胺能神经元的间接影响，以及 RMTg 中 μ-阿片受体在饮酒行为中的作用。该项目将为酒精成瘾特性的新机制提供有价值的信息，并为开发改进的酒精中毒治疗方法提供新的细胞靶点。