Changes in glutamate transmission in the transition to aversion-resistant alcohol drinking

向厌恶饮酒过渡期间谷氨酸传输的变化

• 批准号: 10310676
• 负责人: ERIC A. ENGLEMAN
• 金额: $ 17.28万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-12-01 至 2022-12-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310676
• 关键词: AMPA Receptors; Address; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Animals; Brain region; Characteristics; Chronic; Consumption; Data; Decision Making; Development; Disease; Dose; Ethanol; Excitatory Amino Acid Antagonists; Extinction (Psychology); Family history of; Female; Foundations; Genetic; Genetic Determinism; Genetic Models; Glutamates; Goals; Health Care Costs; Intake; Knowledge; Literature; Measures; Medial; Microdialysis; Microinjections; Modeling; NMDA receptor antagonist; Neurobiology; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacotherapy; Phase; Play; Prefrontal Cortex; Prior Therapy; Quinine; Rattus; Recording of previous events; Relapse; Research; Resistance; Resources; Rewards; Rodent; Rodent Model; Role; Schedule; Signal Transduction; System; Time; United States; Ventral Tegmental Area; Work; addiction; alcohol effect; alcohol preferring rats; alcohol response; alcohol use disorder; antagonist; drinking; effective therapy; extracellular; in vivo; male; metabotropic glutamate receptor 3; neurotransmission; receptor function; response; theories; transmission process; willingness

Project Summary: Changes in glutamate neurotransmission in the transition to aversion-resistant alcohol drinking (CTG) Alcohol use disorders (AUDs) are among the most pervasive and costly health issues in the United States and decades of research has provided strong evidence that genetics, and in particular a family history of alcoholism, plays a pivotal role in the development of AUDs. Alcoholism is a chronic, relapsing, and progressive disorder and a key feature in the transition to alcohol dependence is the development of aversion resistant (ARD) drinking accompanied by a decrease in control of alcohol drinking. The medial prefrontal cortex (MPF) is a center for decision making and receives input from multiple cortical and limbic brain regions. Two sub-regions of the MPF thought to play different roles in the transition to alcohol dependence are the prelimbic (PL) and infralimbic (IL) cortices with activation of PL circuits increasing drug seeking whereas activity in the IL decreases drug seeking after extinction. Current theories of addiction suggest that the transition to compulsive drinking is associated with the emergence of hyper-glutamatergic activity in brain regions receiving significant glutamatergic input from the PL cortex. A common model used to study ARD in rodents is quinine-resistant drinking, where, after a history of ethanol drinking, rodents show a willingness to drink quinine-adulterated ethanol solutions. The alcohol-preferring (P) rat is an excellent resource to model family history of alcoholism in rats, however, no studies have used this resource to investigate the mechanisms underlying quinine-resistant drinking. This represents a critical gap in the literature which we will begin to address in this application. The long-term goal of this project is to identify neurobiological changes associated with the transition to ARD in a suitable model of AUDs. The objective of this component is to determine the role of glutamate transmission within sub-regions of the MPF in the transition to quinine-resistant alcohol drinking using the P-rat as a genetic model of AUDs. The rationale for this work is that by understanding glutamatergic function in all parts of the reward system we can begin to identify mechanisms that underlie the transition to compulsive drinking. The Central Hypothesis states: the transition to quinine-resistant drinking involves increases in the activity of glutamate systems within the PL cortex, but not the IL cortex. AIM 1 studies how alcohol drinking leading to quinine-resistance drinking by P-rats alters glutamate transmission in the IL and PL cortices, as measured by quantitative microdialysis. AIM 2 examines how the development of quinine-resistance drinking changes the in vivo release of glutamate within the PL and IL cortices during alcohol drinking episodes. AIM 3 will examine the effects of local microinjection of ionotropic glutamate receptor antagonists into the PL and IL cortices on ethanol drinking in quinine-resistant vs. quinine-sensitive P-rats. Overall, the results of this component will help lay the foundation for developing pharmacotherapies for treating AUDs. These results will be bi-directionally informative with the other ARC components and as a group will combine to significantly advance the field.

项目摘要：谷氨酸神经传递在向厌恶抵抗转变过程中的变化 饮酒（CTG） 酒精使用障碍 (AUD) 是美国最普遍且代价最高的健康问题之一 数十年的研究提供了强有力的证据，证明遗传因素，特别是家族史 酗酒在 AUD 的发展中起着关键作用。酗酒是一种慢性的、复发性的、 进行性障碍和向酒精依赖过渡的一个关键特征是厌恶的发展 抵抗性（ARD）饮酒伴随着饮酒控制力的下降。内侧前额叶皮层 （MPF）是决策中心，接收来自多个皮质和边缘脑区域的输入。二 MPF 的子区域被认为在向酒精依赖的过渡中发挥不同的作用，它们是前边缘区域 (PL) 和边缘下 (IL) 皮质，PL 回路的激活增加了药物寻找，而 IL 中的活动 减少灭绝后的药物寻找。目前的成瘾理论表明，向强迫性的转变 饮酒与接受显着治疗的大脑区域出现高谷氨酸能活动有关。 来自 PL 皮层的谷氨酸能输入。用于研究啮齿动物 ARD 的常用模型是奎宁抗性的 饮酒，在有饮酒史后，啮齿动物表现出饮用奎宁掺假的意愿 乙醇溶液。嗜酒 (P) 大鼠是模拟酗酒家族史的绝佳资源 然而，没有研究利用这一资源来研究大鼠对奎宁耐药的机制 喝。这代表了文献中的一个关键空白，我们将在本应用程序中开始解决这一空白。这 该项目的长期目标是确定与 ARD 过渡相关的神经生物学变化 澳元的合适模型。该组件的目的是确定谷氨酸传输的作用 在 MPF 的子区域内，使用 P 大鼠作为遗传基因，向奎宁抗性饮酒过渡 澳元模型。这项工作的基本原理是通过了解身体各部分的谷氨酸功能 通过奖励制度，我们可以开始确定向强迫性饮酒过渡的机制。这 中心假说指出：向奎宁抗性饮酒的转变涉及奎宁活性的增加 谷氨酸系统位于 PL 皮质内，但不位于 IL 皮质内。 AIM 1 研究饮酒如何导致 P 大鼠的奎宁抗性饮酒改变了 IL 和 PL 皮质中的谷氨酸传输，测量结果为 定量微透析。 AIM 2 研究了奎宁抗性饮酒的发展如何改变了 饮酒期间 PL 和 IL 皮质内谷氨酸的体内释放。 AIM 3 将检查 离子型谷氨酸受体拮抗剂局部显微注射至 PL 和 IL 皮质的影响 奎宁抗性与奎宁敏感 P 大鼠的乙醇饮用情况。总体而言，该组件的结果将有助于 为开发治疗 AUD 的药物疗法奠定基础。这些结果将是双向的 与其他 ARC 组件一起提供信息，并且作为一个整体将联合起来显着推进该领域的发展。