Glycine regulates ethanol intake

甘氨酸调节乙醇摄入量

• 批准号: 7896171
• 负责人: JIANG-HONG YE
• 金额: $ 24.54万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896171
• 关键词: Action Potentials; Agonist; Alcohol consumption; Alcohol dependence; Alcoholism; Area; Behavior; Brain; Brain region; Cells; Chronic; Collaborations; Consultations; Development; Dopamine; Dose; Electrophysiology (science); Ethanol; Figs - dietary; GLYT1; Glycine; Glycine Receptors; Goals; Injection of therapeutic agent; Intake; Intervention; Laboratories; Lead; Mediating; Microdialysis; Microinjections; Molecular; Nucleus Accumbens; Olives - dietary; Oral; Output; Pathway interactions; Pharmacology; Pilot Projects; Play; Protocols documentation; Rattus; Recording of previous events; Research; Rewards; Role; Scheme; Self Administration; Signal Transduction; Slice; Strychnine; Synapses; System; Training; Work; base; design; dopamine system; dopaminergic neuron; gamma-Aminobutyric Acid; in vivo; inhibitor/antagonist; innovation; insight; interdisciplinary approach; mesolimbic system; neurochemistry; postsynaptic; preference; presynaptic; problem drinker; public health relevance; research study; response; synaptic inhibition; therapy design/development; transmission process

DESCRIPTION (provided by applicant): The mechanism underlying alcohol addiction remains obscure, although it is well documented that the mesolimbic dopamine (DA) system, originating from the ventraltegmental area (VTA) and projecting to the nucleus accumbens (NAc), plays a critical role. The output of VTA DA neurons is normally constrained by powerful GABA-mediated synaptic inhibition. However, little is known about the factors that may govern this important GABAergic synapses. Our long-term goal is to elucidate the regulatory mechanisms controlling the GABAergic synapses as a prerequisite for the development of new therapy of alcoholics. The specific hypothesis behind the proposed research is that the glycine receptors (GlyRs) in the mesolimbic system play a major regulatory role that controls the GABAergic synapses on VTA DA neurons and ethanol intake. Preliminary electrophysiological evidence from our laboratory indicates that GlyRs exist on the GABAergic terminals, which make synapses on VTA DA neurons. Activation of these GlyRs reduces GABAergic transmission and increases VTA DA cell firing. In addition, recent in vivo studies indicate that microinjection of glycine into NAc, or system administration of ORG 25935, an inhibitor of glycine transporter 1, decreases ethanol intake. In this project, we will conduct experiments on rats which are trained for self-administration of ethanol with two-bottle protocol. Specific Aim #1 will assess the effects of VTA GlyRs on voluntary ethanol intake. We will determine the effects of intra-VTA injection of the agonist and/or antagonist of GlyRs on ethanol intake and on NAc DA levels. Specific Aim #2 will characterize the cellular mechanisms of glycine's action. We will assess the electrophysiological signals (e.g. GABAergic inhibitory synaptic currents and action potentials) recorded from VTA DA neurons in brain slices of rats with a long history of ethanol drinking. The result of this multiple disciplinary study may gain new insight into glycine's effects on the brain reward pathways and could lead the development of new therapies of alcoholics. PUBLIC HEALTH RELEVANCE: The mechanism of alcohol addiction remains obscure. Our preliminary studies found that glycine in the mesolimbic system plays an important role in regulating ethanol drinking. This project will investigate the cellular mechanism by which glycine regulates voluntary ethanol drinking. This proposal will bring important information to design rational pharmacotherapeutic interventions in alcoholism.

描述（由申请人提供）：饮酒成瘾的机制仍然晦涩难懂，尽管有充分的文献证明，源自腹膜段（VTA）并投影到伏隔核（NAC）的中唇胶多巴胺（DA）系统起着至关重要的作用。 VTA DA神经元的输出通常受强大的GABA介导的突触抑制的约束。但是，对于可能控制这种重要的GABA能突触的因素知之甚少。我们的长期目标是阐明控制GABA能突触的调节机制，以此作为开发新饮酒疗法的先决条件。拟议的研究背后的特定假设是，中唇系统中的甘氨酸受体（Glyrs）起着主要的调节作用，可控制VTA DA神经元和乙醇摄入的GABA能突触。我们实验室的初步电生理证据表明，Gabaergic末端中存在Glyrs，这使得在VTA DA神经元上成为突触。这些Glyrs的激活减少了GABA能传播并增加了VTA DA细胞的射击。此外，最近的体内研究表明，甘氨酸将甘氨酸显微注射为NAC或甘氨酸转运蛋白1的抑制剂ORG 25935的系统给药可降低乙醇摄入量。在这个项目中，我们将对通过两瓶装方案进行自我管理的大鼠进行实验。具体目标＃1将评估VTA Glyrs对自愿乙醇摄入的影响。我们将确定Glyrs的激动剂和/或拮抗剂对乙醇摄入量和NAC DA水平的影响。特定的目标＃2将表征甘氨酸作用的细胞机制。我们将评估来自乙醇饮用史的大鼠脑切片中VTA DA神经元记录的电生理信号（例如GABA能抑制性突触电流和动作电位）。这项多项纪律研究的结果可能会获得对甘氨酸对大脑奖励途径影响的新见解，并可能导致酗酒者的新疗法的发展。 公共卫生相关性：酒精成瘾的机制仍然晦涩难懂。我们的初步研究发现，中边缘系统中的甘氨酸在调节乙醇饮用中起着重要作用。该项目将研究甘氨酸调节自愿乙醇饮用的细胞机制。该提案将带来重要的信息来设计酒精中毒的理性药物治疗干预措施。