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）：暴饮暴食是美国最普遍的酒精中毒形式，但暴饮暴食的神经生物学并没有得到很好的理解。来自我实验室的大量功能数据表明，酒精诱导的MGLUR5/HOMER2途径活性（通过PI3K和PKC5）在伏隔核（NAC）壳中的增加非常重要，这对于在暴饮暴食的鼠模型中消费酒精的倾向很重要。 NAC壳与扩展的杏仁核子电路的其他成员共享细胞结构，解剖和功能特征，包括杏仁核的中心核（CEA） - 脑区域高度与酒精中毒神经生物学有关。 HOMER2在CEA中富集，其水平与MGLUR1/5的慢性饮酒模型一起上调。初步功能数据表明，正如针对NAC外壳所观察到的，抑制CEA MGLUR5以及PI3K的活性减少了小鼠的暴饮暴食，这一发现与现有的报告有关减少CEA PKC5敲低的有限访问酒精摄入量的报告是一致的。这样的数据表明，在CEA中通过PI3K和PKC5介导的信号传导的重要作用在CEA的调节中，也许是遗传性易受暴饮暴食。 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,暴饮暴食。该提案的目标1将采用药理学和遗传方法的组合来测试特定的假设，即CEA内通过MGLUR5-HOMER2-PI3K和MGLUR5-HOMER2-PKC5途径完整信号传导是必需的和/或足以维持小鼠中过量酒精摄入量的情况。 AIM 2将这些功能研究与饮酒病史对MGLUR5介导的信号通路的表达和激活状态的短期和长期影响有关，及其前杏仁核结构及其前额叶皮层互连区域内的表达和活化状态。 AIM 3将使用几种动物模型将基础和酒精刺激的MGLUR5-HOMER2-激酶途径激活与遗传倾向相关。预计获得的结果将大大提高我们对MGLUR/HOMER2介导的信号在扩展杏仁核中的作用的理解，从而调节了过量饮酒的维持和脆弱性。这种知识将指出酒精诱导的MGLUR5/Homer介导的调节谷氨酸后谷氨酸后传播的调节及其在杏仁核结构内的传播及其前额叶的皮质互连是关键的神经适应性，作为对酒精饮料的高度相关性，对酒精饮料和葡萄酒的相关性，对酒精饮料进行了高度相关性。 公共卫生相关性：反复的酒精管理会引起持续性，兴奋性神经递质谷氨酸的不良适应性变化，其中一些神经适应性对于维持过多的饮酒行为至关重要。因此，对介导扩展的杏仁酸谷氨酸传播的突触后机制反复饮酒的能力涉及的分子机制的理解将有助于鉴定新型的治疗靶标，以治疗酒精中毒，并有助于筛查“筛查”个人治疗或预测个人治疗的态度。为此，该项目将采用行为，遗传和免疫学方法的结合来表征暴饮暴食对MGLUR5介导的信号的短期和长期影响，并在扩展的杏仁核中及其与暴饮暴食脆弱性的关系。