Homer proteins, glutamate and alcoholism

描述（由申请人提供）：反复饮酒的长期行为后果与谷氨酸伏隔核神经传递的改变有关。因此，导致个体易受慢性酒精诱导的大脑和行为变化影响的候选分子可能是调节谷氨酸突触可塑性的分子。这个项目将测试一个重要的假设，即酒精对酒精奖励的遗传易感性与酒精增加荷马家族突触后支架蛋白的表达有关，这些蛋白参与调节谷氨酸突触的可塑性。我们将对两种自愿饮酒倾向不同的小鼠[C57BL/6（高）和DBA/2J（低）]的伏隔核进行体内微透析，以检测基础和酒精诱导的细胞外谷氨酸变化的品系差异。在药理学上控制细胞外谷氨酸水平的同时，对饮酒行为的检查将在这些菌株中建立谷氨酸伏隔核与饮酒倾向之间的因果关系（Specific Aim 1）。将采用免疫印迹法评估伏隔核Homer2蛋白含量的品系差异，并评估调节Homer2蛋白表达对饮酒行为的影响，以确认该蛋白在饮酒中的积极作用（Specific Aim 2）。预计应变差将存在于

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.