mGluR-Homer interactions in excessive drinking

目前的酒精中毒理论认为，酒精诱导的神经适应在边缘结构中， 大脑，包括脑桥核（NAC），有助于从娱乐性饮酒的过渡 to excessive过量alcohol酒精consumption消费.最近，第1组代谢型谷氨酸受体（mGluR）- 相关的支架蛋白Homer 2被鉴定为一种活性和必要的细胞介质， 酒精诱导的小鼠神经可塑性。组成性表达的Homer蛋白促进第1组mGluR- 刺激的细胞内信号传导和突触后密度内的簇1 mGluRs，共定位 这些受体与其他参与突触可塑性的蛋白质，如PI 3 K（磷脂酰肌醇-3 激酶）。Homer 2缺失降低NAC中第1组mGluRs的功能和表达 Homer 2基因敲除小鼠的酒精回避和不耐受行为表型类似于 通过药理学阻断第1组mGluRs产生。总的来说，这些观察 提示组1 mGluR-Homer信号传导是过量酒精重要细胞介质 消费为了直接验证这一假设，本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信号传导在调节中作用的方法 在预定的高酒精消耗（SHAC）鼠模型中过量酒精消耗（Aim 1）。将采用免疫组织化学和免疫印迹方法来确定Homer 2在细胞凋亡中的作用。 n调节持续过量饮酒对NAC突触结构的影响 以及mGluR-Homer信号复合物的形成、亚细胞定位和功能 (Aim 2）。最后，将过量饮酒的遗传变异与mGluR-Homer-PI 3 K表达相关， 和NAC内的信号传导，免疫印迹总蛋白含量和膜定位， 将在小鼠品系之间选择性地比较mGluR-Homer-PI 3 K信号级联的成员 为高SHAC和SLAC（预定低酒精消费）表型而饲养。的结果予以 这些研究将进一步加深我们对参与调节从 娱乐过度饮酒，并提供更深入的了解酒精中毒的病因学及其 治疗

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.