mGluR-Homer interactions in excessive drinking

mGluR-Homer 与过量饮酒的相互作用

基本信息

批准号：
7483230
负责人：
Karen Kathleen Szumlinski
金额：
$ 15.55万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7483230
关键词：
1,2-diacylglycerol 1-Phosphatidylinositol 3-Kinase 7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester Acute Alcohol Phenotype Alcohol consumption Alcoholism Alcohols Amino Acids Architecture Attenuated Behavioral Binding Boutos Brain Breeding Cell membrane Chromosome Pairing Chronic Co-Immunoprecipitations Cocaine Collaborations Complementary DNA Complex Consumption Data Dendritic Spines Dependovirus Development Diglycerides Disease Disruption Dopamine Dose Down-Regulation Drosophila genus Enhancers Etiology Event Exhibits Family Gene Expression Genes Genetic Germany Glutamate Receptor Glutamates Health Sciences Heavy Drinking Heritability Home environment Homer protein Human Immunoblotting Indiana Infusion procedures Inositol Isoenzymes Knock-in Mouse Knockout Mice LY294002 Laboratories Laser Scanning Microscopy Localized Mediating Mediator of activation protein Membrane Messenger RNA Metabotropic Glutamate Receptors Modeling Molecular Morphology Motivation Motor Mus Mutant Strains Mice Mutation N-Methyl-D-Aspartate Receptors Neuronal Plasticity Neurons Nucleus Accumbens Numbers Olives - dietary Oregon Personal Communication Pharmaceutical Preparations Phenotype Phospholipase C Phosphotransferases Photons Play Principal Investigator Proline Protein Family Proteins RNA Interference RNA Splicing Receptor Activation Regulation Research Research Personnel Rodent Role Scaffolding Protein Schedule Screening procedure Series Shipping Ships Signal Transduction Site Small Interfering RNA Structure Subfamily lentivirinae Synapses Synaptic plasticity Testing Texas Tissues Transfection Transgenic Mice Universities Variant Welts alcohol effect austin base density design drinking drinking behavior drinking water gene interaction in vivo insight kinase inhibitor medical schools member metabotropic glutamate receptor type 1 neuroadaptation neurochemistry neuropsychiatry neurotransmission novel postsynaptic programs protein expression receptor receptor expression receptor function research study theories tripolyphosphate

项目摘要

Current theories of alcoholism posit that alcohol-induced neuroadaptations within limbic structures in the brain, including the nucleus accumbens (NAC), contribute to the transition from recreational alcohol drinking to excessivealcohol consumption. Recently, the Group 1 metabotropic glutamate receptor (mGluR)- associated scaffolding protein Homer2 was identified as an active and necessary cellular mediator of alcohol-induced neural plasticity in mice. Constitutively expressed Homer proteins facilitate Group 1 mGluR- stimulated intracellular signaling and cluster Group 1 mGluRs within the postsynaptic density, co-localizing these receptorswith other proteins implicated in synaptic plasticity, such as PI3K (phosphatiylionsitol-3 kinase). Homer2 deletion reduces the function and the expression of Group 1 mGluRs in the NAC in vivo and the alcohol-avoiding and -intolerant behavioral phenotype of Homer2 knock-out (KO) mice resembles that produced by the pharmacological blockade of Group 1 mGluRs. Collectively, these observations suggest that Group 1 mGluR-Homer signaling is an important cellular mediator of excessive alcohol consumption. To test this hypothesis directly, this proposal will employ in vivo pharmacological and genetic approaches to characterizethe role for Group 1 mGluR-Homer signaling within the NAC in regulating excessive alcohol consumption within the scheduled high alcohol consumption (SHAC) murine model (Aim 1). Immunohistochemical and immunoblotting approaches will be employed to determine the role for Homer2 n regulating the effects of sustained, excessivealcohol consumption upon the synaptic architecture of NAC neurons, as well as the formation, subcellular localization and function of mGluR-Homer signaling complexes (Aim 2). Finally, to relate genetic variance in excessive alcohol drinking to mGluR-Homer-PI3K expression and signaling within the NAC, immunoblotting the total protein content and membrane localization of members of the mGluR-Homer-PI3K signaling cascade will be compared between mouse lines selectively bred for high SHAC and SLAC (Scheduled Low Alcohol Consumption) phenotypes. The results of these studies will further our understanding of the cellular mechanisms involved in regulating the transition from recreational to excessive alcohol drinking and provide greater insight into the etiology of alcoholism and its treatment.

当前的酒精中毒理论认为，酒精诱导的大脑边缘结构内的神经适应大脑，包括伏隔核（NAC），有助于从娱乐性饮酒的转变过度饮酒。最近，第 1 组代谢型谷氨酸受体 (mGluR)- 相关支架蛋白 Homer2 被确定为活性和必要的细胞介质酒精诱导的小鼠神经可塑性。组成型表达的 Homer 蛋白促进第 1 组 mGluR- 刺激细胞内信号传导和突触后密度内的第 1 组 mGluR 簇，共定位这些受体与其他与突触可塑性有关的蛋白质，例如 PI3K（磷酸肌醇 3）激酶）。 Homer2 缺失会降低体内 NAC 中第 1 组 mGluR 的功能和表达 Homer2 敲除 (KO) 小鼠的戒酒和不耐受行为表型类似于由第 1 组 mGluR 的药理学阻断产生的。总的来说，这些观察表明第 1 组 mGluR-Homer 信号传导是过量酒精的重要细胞介质消耗。为了直接检验这一假设，该提案将采用体内药理学和遗传学方法表征 NAC 内第 1 组 mGluR-Homer 信号传导在调节中的作用的方法在预定的高酒精消耗量（SHAC）小鼠模型中过量饮酒（Aim 1）。将采用免疫组织化学和免疫印迹方法来确定 Homer2 的作用 n 调节持续过量饮酒对 NAC 突触结构的影响神经元，以及 mGluR-Homer 信号复合物的形成、亚细胞定位和功能（目标 2）。最后，将过量饮酒的遗传变异与 mGluR-Homer-PI3K 表达联系起来和 NAC 内的信号传导，对总蛋白含量和膜定位进行免疫印迹 mGluR-Homer-PI3K 信号级联的成员将在小鼠品系之间进行选择性比较专为高 SHAC 和 SLAC（预定低酒精消耗）表型而培育。这些结果研究将进一步加深我们对调节从细胞到细胞的转变所涉及的细胞机制的理解。娱乐性的过度饮酒，并提供对酒精中毒的病因学及其病因的更深入的了解治疗。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

mGluR1 within the nucleus accumbens regulates alcohol intake in mice under limited-access conditions.

DOI：
10.1016/j.neuropharm.2014.01.024
发表时间：
2014-04
期刊：
Neuropharmacology
影响因子：
4.7
作者：
Lum EN;Campbell RR;Rostock C;Szumlinski KK
通讯作者：
Szumlinski KK

Homer2 regulates alcohol and stress cross-sensitization.

DOI：
10.1111/adb.12252
发表时间：
2016-05
期刊：
Addiction biology
影响因子：
3.4
作者：
Quadir SG;Santos JR;Campbell RR;Wroten MG;Singh N;Holloway JJ;Bal SK;Camarini R;Szumlinski KK
通讯作者：
Szumlinski KK