Urocortin, Edinger-Westphal nucleus & EtOH consumption

尿皮质素，Edinger-Westphal 核

• 批准号: 6852698
• 负责人: Andrey E Ryabinin
• 金额: $ 20.76万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-10 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6852698
• 关键词: alcoholic beverage consumption; alcoholism /alcohol abuse; autoradiography; behavior test; behavioral /social science research tag; behavioral genetics; brain regulatory center; corticotropin releasing factor; gene expression; genetic strain; hormone receptor; immunocytochemistry; in situ hybridization; laboratory mouse; neuropeptides; psychopharmacology; regulatory gene; reinforcer; transcription factor

DESCRIPTION (provided by applicant): The mechanisms regulating alcohol consumption in large part are not well understood. A number of research groups have analyzed expression of inducible transcription factors (ITFs) to identify alcohol-sensitive brain regions. Early studies observed changes in expression of ITF c-Fos in a substantial number of brain regions after involuntary alcohol administration in rodents. In contrast, voluntary alcohol self-administration in rodents leads to c-Fos expression in a much smaller number of brain regions. Importantly, in these paradigms robust induction of c-Fos occurs only in the Edinger-Westphal nucleus (EW). EW is a compact brain structure involved in oculomotor adaptation, nociception, regulation of metabolism, feeding, body temperature and anxiety. This nucleus has gained attention as the primary source of neuropeptide urocortin (Ucn). Recent studies show that inbred strains of mice known for differences in alcohol consumption, and mice genetically selected to differ in measures of alcohol reward differ dramatically in the number of Ucn cells in EW. We hypothesize that the brain Ucn system contributes to regulation of alcohol consumption, and that this regulation occurs via EW projection to the lateral septum (LS). To test this hypothesis four Specific Aims are proposed. 1. To confirm relation between level of Ucn in EW and alcohol consumption in a genetically heterogeneous population of mice and in congenic mice carrying chromosomal loci regulating alcohol preference. 2. To investigate the effects of EW lesions on alcohol consumption in mice. 3. To investigate the role of Ucn projections to LS in alcohol consumption using retrograde neuroanatomical tracing and microinjection of Ucn and its antagonists into LS. 4. To investigate the effects of ethanol exposure on the level and activity of the CRH-R2 receptors in LS, and in the level of Ucn mRNA in EW (using receptor autoradiography and in situ hybridization). The long-term goal of these studies is to understand the mechanisms regulating alcohol consumption. Such knowledge is important for development of pharmacotherapy of alcoholism

描述（由申请人提供）：对调节饮酒的机制在很大程度上尚不清楚。许多研究组分析了诱导转录因子（ITF）的表达，以鉴定对酒精敏感的大脑区域。早期研究观察到啮齿动物非自愿性饮酒后，在大量大脑区域中ITF C-FO的表达变化。相比之下，啮齿动物中的自愿性酒精自给自足会导致较少数量的大脑区域的C-FOS表达。重要的是，在这些范式中，C-Fos的稳健诱导仅发生在Edinger-Westphal核（EW）中。 EW是一种紧凑的大脑结构，涉及动眼运动，伤害感受，代谢，喂养，体温和焦虑。该细胞核已成为神经肽尿素素（UCN）的主要来源。最近的研究表明，以酒精消耗差异而闻名的小鼠的近交菌株，在遗传中选择的小鼠在酒精奖励的测量中有所不同，而EW中的UCN细胞数量却差异很大。我们假设大脑UCN系统有助于调节酒精消耗，并且该调节是通过EW投射到侧隔隔隔（LS）的。为了检验该假设，提出了四个具体目标。 1。确认EW中UCN水平与饮酒水平之间的关系，在遗传异质种群的小鼠和携带调节酒精偏爱的染色体基因座的同类小鼠中。 2。研究EW病变对小鼠饮酒的影响。 3。研究UCN对LS在饮酒中的作用，使用UCN及其拮抗剂对LS的逆行神经解剖学痕迹和对LS的显微注射。 4。研究乙醇暴露对LS中CRH-R2受体水平和活性的影响，以及在EW中的UCN mRNA水平（使用受体放射率和原位杂交）。 这些研究的长期目标是了解调节饮酒的机制。这种知识对于开发酒精中毒很重要