Urocortin, Edinger-Westphal nucleus & EtOH consumption

尿皮质素，Edinger-Westphal 核

• 批准号: 6732414
• 负责人: Andrey E Ryabinin
• 金额: $ 20.39万
• 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/6732414
• 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）：调节酒精消费的机制在很大程度上尚不清楚。许多研究小组分析了诱导转录因子（ITF）的表达，以识别酒精敏感的大脑区域。早期研究观察到啮齿类动物非自愿饮酒后，大量大脑区域的 ITF c-Fos 表达发生变化。相比之下，啮齿类动物自愿自行饮酒会导致 c-Fos 在较少数量的大脑区域中表达。重要的是，在这些范例中，c-Fos 的强烈诱导仅发生在 Edinger-Westphal 核 (EW) 中。 EW 是一种紧凑的大脑结构，涉及动眼适应、伤害感受、新陈代谢调节、进食、体温和焦虑。该核作为神经肽尿皮质素 (Ucn) 的主要来源而受到关注。最近的研究表明，已知饮酒量存在差异的近交系小鼠，以及经过基因选择而具有不同酒精奖励措施的小鼠，EW 中的 Ucn 细胞数量存在显着差异。我们假设大脑 Ucn 系统有助于调节饮酒量，并且这种调节是通过 EW 投射到侧中隔 (LS) 来实现的。为了检验这一假设，提出了四个具体目标。 1. 确认遗传异质小鼠群体和携带调节酒精偏好的染色体位点的同源小鼠中 EW 中的 Ucn 水平与饮酒量之间的关系。 2. 探讨EW损伤对小鼠饮酒量的影响。 3. 通过逆行神经解剖追踪和将 Ucn 及其拮抗剂显微注射到 LS 中，研究 Ucn 对 LS 的预测在饮酒中的作用。 4. 研究乙醇暴露对LS中CRH-R2受体水平和活性以及EW中Ucn mRNA水平的影响（使用受体放射自显影和原位杂交）。 这些研究的长期目标是了解调节饮酒的机制。这些知识对于酒精中毒药物治疗的发展很重要