Glycine regulates ethanol intake

甘氨酸调节乙醇摄入量

• 批准号: 8046489
• 负责人: JIANG-HONG YE
• 金额: $ 18.53万
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046489
• 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; 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）：酒精成瘾的机制仍然不清楚，尽管有充分证据表明，起源于腹侧被盖区（VTA）并投射到伏隔核（NAc）的中脑边缘多巴胺（DA）系统在酒精成瘾中发挥着关键作用。角色。 VTA DA 神经元的输出通常受到强大的 GABA 介导的突触抑制的限制。然而，人们对控制这一重要 GABA 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，作为开发酗酒者新疗法的先决条件。这项研究背后的具体假设是，中脑边缘系统中的甘氨酸受体 (GlyR) 发挥着重要的调节作用，控制 VTA DA 神经元上的 GABA 能突触和乙醇摄入。我们实验室的初步电生理学证据表明，GlyR 存在于 GABA 能末端，这些末端在 VTA DA 神经元上形成突触。这些 GlyR 的激活会减少 GABA 能传递并增加 VTA DA 细胞放电。此外，最近的体内研究表明，将甘氨酸显微注射到 NAc 中，或系统施用 ORG 25935（甘氨酸转运蛋白 1 的抑制剂）可减少乙醇摄入量。在这个项目中，我们将对经过两瓶方案自我注射乙醇训练的大鼠进行实验。具体目标#1 将评估 VTA GlyR 对自愿乙醇摄入量的影响。我们将确定 VTA 内注射 GlyR 激动剂和/或拮抗剂对乙醇摄入量和 NAc DA 水平的影响。具体目标#2 将描述甘氨酸作用的细胞机制。我们将评估长期饮酒的大鼠脑切片中 VTA DA 神经元记录的电生理信号（例如 GABA 抑制性突触电流和动作电位）。这项多学科研究的结果可能会对甘氨酸对大脑奖励途径的影响有新的认识，并可能导致酗酒者新疗法的开发。 公共卫生相关性：酒精成瘾的机制仍然不清楚。我们的初步研究发现，中脑边缘系统中的甘氨酸在调节乙醇饮用方面发挥着重要作用。该项目将研究甘氨酸调节自愿乙醇饮用的细胞机制。该提案将为设计合理的酗酒药物治疗干预措施提供重要信息。