Catecholamine Transcriptional Regulation and Response t*

生物体对酒精消耗的神经反应涉及广泛的 细胞间通讯、信号转导通路的激活以及 基因转录的变化。反应的复杂性阻碍了 达到对关键事件的基本机械理解。最近， 遗传分析和技术的进步使人们能够评估 个体基因对酒精消耗的反应。利用遗传 技术，发现缺乏合成能力的小鼠 神经递质去甲肾上腺素（NE）对乙醇的反应发生改变 局这些小鼠对乙醇的偏好降低 自我给药并且对乙醇的镇静作用更敏感， 提示NE在神经系统对乙醇的反应中的作用。 不相关的研究发现， 乙醇导致相应的mRNA和蛋白质的特异性升高， 多巴胺β-羟化酶 (DBH它催化多巴胺和酪氨酸产生NE 羟化酶（TH），负责多巴的形成。的重点 应用是进一步了解细胞对乙醇的反应， 涉及的成分的识别和表征 DBH和TH基因的转录调控。此外，该提案 旨在进一步探讨NE参与转录调控的机制， 适应乙醇。具体目标是：（1）定义乙醇响应 大鼠TH和DBH基因的遗传调控元件，以及 与这些元素结合的因素。(2)评估NE的重要性 神经传递对酒精反应性的体内比较基因 杏仁核、腹侧被盖和延髓核的表达模式 野生型和DBH缺陷小鼠之间的差异。(3)描述 TH和DBH基因对小鼠中枢神经系统中急性和慢性乙醇给药的影响。 这些实验的结果将进一步加深我们对NE作用的理解。 细胞对酒精适应中的合成和神经传递 治疗

The neural response of organisms to alcohol consumption involves extensive cell-cell communication, activation of signal transduction pathways and changes in gene transcription. The complexity of the response has hindered reaching basic mechanistic understandings of the critical events. Recently, advances in genetic analysis and technology allow the evaluation of the role of an individual gene in the response to alcohol consumption. Using genetic technology, it was found that mice lacking the ability to synthesize the neurotransmitter norepinephrine (NE) exhibit altered responses to ethanol administration. These mice have reduced preference for ethanol self-administration and are more sensitive to the sedative effects of ethanol, suggesting a role for NE in the response of the nervous system to ethanol. Unrelated studies found that treatment of neuroblastoma cell cultures with ethanol resulted in a specific elevation of mRNAs and proteins corresponding to two enzymes involved in the biosynthesis of NE, dopamine beta-hydroxylase (DBH which catalyzes the production of NE from dopamine, and tyrosine hydroxylase (TH), responsible for the formation of DOPA. The focus of this application is to further understand the cellular response to ethanol by identification and characterization of the components involved in transcriptional regulation of the DBH and TH genes. In addition, this proposal is designed to further explore the involvement of NE in the transcriptional adaptation to ethanol. The specific aims are to: (1) Define the ethanol-responsive genetic regulatory elements of the rat TH and DBH genes, and the factors which bind to those elements. (2) Evaluate the importance of NE neurotransmission to alcohol responsiveness in vivo by comparing gene expression patterns in the amygdala, ventral tegmentum and nucleus accumbans between wild type and DBH deficient mice. (3) Characterize the response of the TH and DBH genes to acute and chronic ethanol administration in the mouse CNS. The results of these experiments will further our understanding of the role NE synthesis and neurotransmission in the cellular adaptation to alcohol treatment.