Homer proteins, glutamate and alcoholism

描述(由申请人提供)：伏隔核谷氨酸神经传递的改变与反复饮酒的长期行为后果有关。因此，导致个体容易受到慢性酒精诱导的大脑和行为改变的分子候选很可能是那些调节谷氨酸突触可塑性的分子。该项目将检验这一总体假设，即对酒精奖励的遗传脆弱性与酒精增强突触后支架蛋白Hmer家族的表达有关，该家族参与调节谷氨酸能突触的可塑性。在体内，将在自愿饮酒倾向不同的两种品系的小鼠的伏隔核进行微透析[C57BL/6(高)和DBA/2J(低)]，以检查基础和酒精诱导的细胞外谷氨酸的品系差异。在药理上操纵细胞外谷氨酸水平的同时对饮酒行为的检查将建立这些菌株中伏隔物谷氨酸和饮酒倾向之间的因果关系(特定目标1)。免疫印迹将被用来评估伏隔蛋白2蛋白含量的菌株差异，并将评估操纵Hmer 2蛋白表达对饮酒行为的影响，以确认该蛋白在酒精消费中的积极作用(特定目标2)。预计将存在应变差异， 基础和酒精诱导的谷氨酸传递和伏隔水平的改变 霍梅尔2。此外，预计大量饮酒的遗传倾向将服从伏隔核细胞外谷氨酸水平的变化，以及伏隔核荷马蛋白表达的变化。这些研究的结果将有助于深入了解荷马蛋白在酒精奖励遗传易感性中的作用，并将增进我们对酒精中毒个体易感性背后的神经可塑性调节的细胞机制的理解。

DESCRIPTION (provided by applicant): Alterations in accumbens glutamate neurotransmission are implicated in the long-term behavioral consequences of repeated alcohol administration. Thus, molecular candidates contributing to individual vulnerability to chronic alcohol-induced changes in brain and behavior are likely those regulating plasticity at glutamate synapses. This project will test the over-arching hypothesis that genetic vulnerability to alcohol reward is related to the capacity of alcohol to augment the expression of the Homer family of post-synaptic scaffolding proteins involved in modulating plasticity at glutamatergic synapses. In vivo microdialysis will be conducted in the nucleus accumbens of two strains of mice that differ in their propensity to voluntarily consume alcohol [C57BL/6 (high) and DBA/2J (low)] to examine for strain differences in basal and alcohol induced changes in extra cellular glutamate. An examination of drinking behavior while pharmacologically manipulating extra cellular glutamate levels will establish a causal relationship between accumbens glutamate and the propensity to consume alcohol in these strains (Specific Aim 1). Immunoblotting will be employed to assess for strain differences in accumbens Homer2 protein content and the effects of manipulating Homer2 protein expression will be assessed on drinking behavior to confirm an active role for this protein in alcohol consumption (Specific Aim 2). It is expected that a strain difference will exist with respect to basal and alcohol-induced alterations in glutamate transmission and accumbens levels of Homer2. Moreover, it is expected that the genetic propensity to consume large amounts of alcohol will be amenable to changes in accumbens levels of extra cellular glutamate, as well as alterations in accumbens Homer protein expression. The results of these studies will provide insight into the role for Homer proteins in genetic vulnerability to alcohol reward and will increase our understanding of the cellular mechanisms mediating the neural plasticity underlying individual vulnerability to alcoholism.