Molecular regulation of CeA glutamate and binge drinking

CeA 谷氨酸和酗酒的分子调控

• 批准号: 7894034
• 负责人: Karen Kathleen Szumlinski
• 金额: $ 35.37万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894034
• 关键词: Address; Alcohol consumption; Alcoholism; Alcohols; Amygdaloid structure; Animal Model; Basal Ganglia; Behavioral; Behavioral Genetics; Brain; Brain region; Cell Nucleus; Chronic; Data; Funding; Genes; Genetic; Genetic Predisposition to Disease; Glutamates; Goals; Grant; Heavy Drinking; Homer protein; Immunoblotting; Immunologic Techniques; Individual; Isoenzymes; Knock-out; Knowledge; Laboratories; Long-Term Effects; Maintenance; Mediating; Modeling; Molecular; Mus; National Institute on Alcohol Abuse and Alcoholism; Nature; Neurobiology; Neurotransmitters; Nucleus Accumbens; Pathway interactions; Pharmacotherapy; Phosphotransferases; Process; Protein Kinase C; Recording of previous events; Regulation; Relapse; Reporting; Request for Proposals; Research Project Grants; Risk; Role; Screening procedure; Series; Signal Pathway; Signal Transduction; Signaling Protein; Structure; Structure of terminal stria nuclei of preoptic region; Testing; Training; Transgenic Organisms; Treatment outcome; United States; addiction; alcoholism therapy; binge drinking; chronic alcohol ingestion; drinking behavior; indexing; insight; knock-down; member; neuroadaptation; neurochemistry; new therapeutic target; postsynaptic; protein kinase C kinase; public health relevance; receptor; relating to nervous system; transmission process

DESCRIPTION (provided by applicant): Binge alcohol drinking is the most prevalent form of alcoholism within the United States yet the neurobiology of binge drinking is not well-understood. A significant body of functional data from my laboratory demonstrates that alcohol-induced increases in mGluR5/Homer2 pathway activity (via PI3K and PKC5) within the nucleus accumbens (NAC) shell as important for the propensity to consume alcohol in murine models of binge alcohol drinking. The NAC shell shares cytoarchitectural, anatomical and functional features with other members of the extended amygdala subcircuit, including the central nucleus of the amygdala (CeA) - a brain region highly implicated in the neurobiology of alcoholism. Homer2 is enriched in the CeA and its levels are up-regulated in concert with those of mGluR1/5 in models of chronic alcohol drinking. Preliminary functional data indicates that, as observed for the NAC shell, inhibiting CeA mGluR5, as well as PI3K, activity reduces binge alcohol drinking in mice, a finding consistent with existing reports for a reduction in limited access alcohol intake upon CeA PKC5 knock-down. Such data point to an important role also for mGluR5-mediated signaling through both PI3K and PKC5 within the CeA in the regulation of, and perhaps genetic vulnerability to, binge drink. This project will expand upon these recent observations and employ our combination of behavioral pharmacological and genetic approaches to test the over-arching hypothesis that idiopathic or alcohol-induced increases in mGluR-mediated signaling through its 1q subunit to PKC5 and its 23 subunit to PI3K within extended amygdala structures, notably the CeA, is important for the manifestation of, and genetic vulnerability to, binge alcohol drinking. Aim 1 of this proposal will employ a combination of pharmacological and genetic approaches to test the specific hypothesis that intact signaling through the mGluR5-Homer2-PI3K and mGluR5-Homer2-PKC5 pathways within the CeA is necessary and/or sufficient for maintaining excessive alcohol intake in mice. Aim 2 will relate these functional studies to the short- and long-term effects of a history of binge drinking upon the expression and activational state of mGluR5-mediated signaling pathways within extended amygdala structures and their prefrontal cortical interconnected regions. Aim 3 will relate basal and alcohol-stimulated mGluR5-Homer2-kinase pathway activation to genetic propensity to binge drink, using several animal models. It is anticipated that the results obtained will greatly increase our understanding of the role for mGluR/Homer2-mediated signaling within the extended amygdala regulates the maintenance of, and vulnerability to, excessive alcohol drinking. Such knowledge will point to alcohol-induced alterations in mGluR5/Homer-mediated regulation of post-synaptic aspects of glutamate transmission within extended amygdala structures and their prefrontal cortical interconnections as critical neuroadaptations regulating the propensity to binge drink, which has high relevance for understanding of alcoholism vulnerability and its treatment with glutamate-targeting pharmacotherapies. PUBLIC HEALTH RELEVANCE: Repeated alcohol administration induces persistent, maladaptive changes in the excitatory neurotransmitter glutamate within the extended amygdala and some of these neuroadaptations are central to maintaining excessive alcohol drinking behavior. Thus, an understanding of the molecular mechanisms involved in the capacity of repeated bouts of binge alcohol drinking upon the postsynaptic mechanisms mediating extended amygdala glutamate transmission will assist in the identification of novel therapeutic targets for the treatment of alcoholism, as well as assist in screening "at risk" individuals or predicting individual treatment outcomes. To this end, this project will employ a combination of behavioral, genetic and immunological approaches to characterize the short- and long-term influences of binge drinking upon mGluR5-mediated signaling within the extended amygdala and its relation to binge drinking vulnerability.

描述（由申请人提供）：酗酒是美国最普遍的酒精中毒形式，但酗酒的神经生物学尚未得到充分理解。来自我实验室的大量功能数据表明，酒精诱导的mGluR 5/Homer 2通路活性增加（通过PI 3 K和PKC 5）在神经核（NAC）壳内对于酗酒小鼠模型中饮酒倾向的重要性。NAC壳与扩展杏仁核子回路的其他成员共享细胞结构，解剖学和功能特征，包括杏仁核中央核（CeA）-一个与酒精中毒神经生物学高度相关的大脑区域。Homer 2富含CeA，其水平在慢性饮酒模型中与mGluR 1/5的水平一致上调。初步功能数据表明，如对于NAC壳所观察到的，抑制CeA mGluR 5以及PI 3 K活性减少了小鼠中的酗酒，这一发现与CeA PKC 5敲低后限制性酒精摄入减少的现有报道一致。这些数据也指出了mGluR 5介导的信号传导通过CeA内的PI 3 K和PKC 5在调节暴饮暴食中的重要作用，以及可能的遗传易感性。该项目将扩展这些最近的观察，并采用我们的行为药理学和遗传学方法相结合，以测试过度兴奋的假设，即特发性或酒精诱导的mGluR介导的信号转导增加，通过其1 q亚基到PKC 5和其23亚基到PI 3 K在扩展杏仁核结构，特别是CeA，是重要的表现，和遗传易感性，酗酒。本提案的目的1将采用药理学和遗传学方法的组合来测试特定假设，即通过CeA内的mGluR 5-Homer 2-PI 3 K和mGluR 5-Homer 2-PKC 5途径的完整信号传导对于维持小鼠过量酒精摄入是必要的和/或足够的。目的2将这些功能研究的短期和长期的影响，酗酒的历史后的表达和激活状态的mGluR 5介导的信号通路内扩展杏仁核结构和他们的前额叶皮层相互连接的地区。目的3将使用几种动物模型将基础和酒精刺激的mGluR 5-Homer 2-激酶通路激活与酗酒的遗传倾向联系起来。预计所获得的结果将大大增加我们对mGluR/Homer 2介导的信号传导在扩展杏仁核内调节过度饮酒的维持和脆弱性的作用的理解。这些知识将指出，酒精诱导的mGluR 5/Homer介导的调节突触后方面的谷氨酸传输的杏仁核结构和其前额叶皮层互连的关键神经适应性调节酗酒的倾向，这具有高度相关性的酒精中毒的脆弱性和谷氨酸靶向药物治疗的理解。 公共卫生关系：反复饮酒会导致杏仁核内兴奋性神经递质谷氨酸的持续性适应不良变化，其中一些神经适应是维持过度饮酒行为的关键。因此，了解的分子机制参与的能力反复发作的酗酒后，突触后机制介导的杏仁核谷氨酸传输延长将有助于识别新的治疗目标，用于治疗酒精中毒，以及协助筛选“风险”的个人或预测个人的治疗结果。为此，该项目将采用行为，遗传和免疫学方法相结合的特点，短期和长期的影响，酗酒后mGluR 5介导的信号在扩展杏仁核及其关系，酗酒的脆弱性。