CFR signaling in stress- and dependence- induced ethanol consumption

压力和依赖性诱导的乙醇消耗中的 CFR 信号传导

• 批准号: 7613627
• 负责人: EMILY Geyer LOWERY-GIONTA
• 金额: $ 2.96万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7613627
• 关键词: Acute; Address; Agonist; Alcohol consumption; Amygdaloid structure; Animals; Attenuated; BALB/cJ Mouse; Brain region; CP 154526; CRF receptor type 1; CRF receptor type 2; Clinical; Condition; Consumption; Corticotropin-Releasing Hormone; Dependence; Development; Disease; Drug Delivery Systems; Ethanol; Ethanol dependence; Exposure to; Heavy Drinking; Infusion procedures; Knowledge; Literature; Mediating; Mus; Neurobiology; Peripheral; Pharmacological Treatment; Phenotype; Publishing; Receptor Signaling; Recording of previous events; Reporting; Research; Role; Signal Transduction; Site; Specificity; Stress; Swimming; Testing; Withdrawal; alcohol response; neuroadaptation; research study; response; urocortin; vapor

DESCRIPTION (provided by applicant): Recent evidence suggests that corticotropin releasing factor (CRF) is involved in excessive voluntary ethanol consumption in ethanol dependent animals, as well as stress-induced increases in ethanol consumption in nondependent animals, via CRF1 and CRF2 receptor signaling. Indeed, recent research explores the use of drugs that target CRF as a potential treatment for conditions associated with excessive alcohol consumption. Since CRF signaling appears to underlie neurobiological responses to ethanol involving histories of stress exposure or dependence, it is possible that increased ethanol consumption associated with these responses reflects significant neuroadaptations in common brain regions containing CRF, like the amygdala. Therefore, the guiding hypothesis of this proposal is that increases in ethanol consumption associated with stress and ethanol dependence are mediated by CRF signaling in the amygdala via the CRF1 and CRF2 receptors. To investigate the role of CRF1 and CRF2 signaling in the expression of dependence-induced increases in ethanol consumption in C57BL/6J mice, the CRF1 receptor antagonist CP-154,526 will be administered peripherally and centrally and the CRF2 receptor agonist will be administered centrally following exposure to multiple cycles of ethanol vapor and withdrawal. To investigate the role of amygdalar CRF in the acquisition/expression of dependence-induced increases in ethanol consumption in C57BL/6J mice, site-directed infusions of CRF-SAP will be administered prior to exposure to multiple cycles of ethanol vapor and withdrawal and limited free access to ethanol. To investigate the role of amygdalar CRF in the acquisition/expression of stress-induced increases in ethanol consumption in BALB/cJ mice, site-directed infusions of CRF-SAP will be administered prior to exposure to forced swim stress and continuous free access to ethanol. The role of CRF signaling, via the CRF1 and CRF2 receptors, as well as amygdalar CRF signaling will be further assessed by these experiments. Although there is some evidence to suggest CRF signaling is involved in dependence-induced ethanol consumption in mice, to date there are only a few published reports investigating the role of the CRF1R, and, to the best of our knowledge, no published reports investigating the role of the CRF2R in mice with a history of ethanol dependence. Additionally, to date, the role of amygdalar CRF in stress-induced ethanol consumption has not been investigated. Therefore, these experiments will extend the current literature on the role of CRF in ethanol-related phenotypes to mice and thereby aid in the development of clinical and pharmacological treatments for disorders characterized by excessive ethanol consumption.

描述（由申请人提供）：最近的证据表明，促肾上腺皮质激素释放因子（CRF）通过 CRF1 和 CRF2 受体信号传导参与乙醇依赖动物的过度自愿乙醇消耗，以及非依赖动物的压力诱导的乙醇消耗增加。事实上，最近的研究探索了使用针对 CRF 的药物作为治疗过度饮酒相关疾病的潜在疗法。由于 CRF 信号传导似乎是对乙醇的神经生物学反应的基础，涉及压力暴露或依赖的历史，因此与这些反应相关的乙醇消耗增加可能反映了含有 CRF 的常见大脑区域（如杏仁核）的显着神经适应。因此，该提议的指导性假设是，与压力和乙醇依赖相关的乙醇消耗增加是由杏仁核中的 CRF 信号通过 CRF1 和 CRF2 受体介导的。为了研究 CRF1 和 CRF2 信号在 C57BL/6J 小鼠依赖性诱导的乙醇消耗增加表达中的作用，将外周和中枢施用 CRF1 受体拮抗剂 CP-154,526，并在暴露后中枢施用 CRF2 受体激动剂乙醇蒸汽和抽出的多个循环。为了研究杏仁核 CRF 在 C57BL/6J 小鼠中依赖性诱导的乙醇消耗增加的获得/表达中的作用，将在暴露于乙醇蒸汽的多个周期和戒断和限制之前进行 CRF-SAP 的定点输注。免费获得乙醇。为了研究杏仁核 CRF 在 BALB/cJ 小鼠压力诱导的乙醇消耗增加的获得/表达中的作用，在暴露于强迫游泳压力和持续自由获取乙醇之前，将进行 CRF-SAP 的定点输注。通过 CRF1 和 CRF2 受体以及杏仁核 CRF 信号传导的 CRF 信号传导的作用将通过这些实验得到进一步评估。尽管有一些证据表明 CRF 信号传导参与小鼠依赖性诱导的乙醇消耗，但迄今为止，只有少数发表的报告调查 CRF1R 的作用，并且据我们所知，还没有发表的报告调查 CRF1R 的作用。 CRF2R 在有乙醇依赖史的小鼠中的作用。此外，迄今为止，杏仁核 CRF 在应激诱导的乙醇消耗中的作用尚未得到研究。因此，这些实验将把目前关于 CRF 在乙醇相关表型中的作用的文献扩展到小鼠，从而有助于开发针对以过量乙醇消耗为特征的疾病的临床和药理学治疗方法。