CFR signaling in stress- and dependence- induced ethanol consumption

描述（由申请方提供）：最近的证据表明，促肾上腺皮质激素释放因子（CRF）通过CRF 1和CRF 2受体信号传导参与乙醇依赖性动物的过量自愿乙醇消耗，以及非依赖性动物的应激诱导乙醇消耗增加。事实上，最近的研究探索了使用针对CRF的药物作为与过度饮酒相关的疾病的潜在治疗方法。由于CRF信号似乎是对乙醇的神经生物学反应的基础，涉及应激暴露或依赖的历史，因此与这些反应相关的乙醇消耗量增加可能反映了包含CRF的常见脑区（如杏仁核）的显著神经适应。因此，该建议的指导假设是，与压力和乙醇依赖相关的乙醇消耗量增加是由杏仁核中的CRF信号通过CRF 1和CRF 2受体介导的。为了研究C57 BL/6 J小鼠中CRF 1和CRF 2信号传导在依赖性诱导的乙醇消耗增加的表达中的作用，在暴露于多个乙醇蒸气和戒断循环后，将外周和中心给予CRF 1受体拮抗剂CP-154，526，并将中心给予CRF 2受体激动剂。为了研究杏仁核CRF在C57 BL/6 J小鼠中获得/表达依赖性诱导的乙醇消耗增加中的作用，在暴露于多个循环的乙醇蒸汽和戒断以及有限的自由获取乙醇之前，将施用CRF-SAP的定点输注。为了研究杏仁核CRF在BALB/cJ小鼠中获得/表达应激诱导的乙醇消耗增加中的作用，在暴露于强迫游泳应激和连续自由获取乙醇之前，将施用CRF-SAP的定点输注。CRF信号传导的作用，通过CRF 1和CRF 2受体，以及杏仁CRF信号传导将进一步评估这些实验。虽然有一些证据表明CRF信号参与了依赖诱导的小鼠乙醇消耗，但迄今为止，只有少数已发表的研究CRF 1 R作用的报告，据我们所知，没有发表研究CRF 2 R在有乙醇依赖史的小鼠中作用的报告。此外，到目前为止，杏仁核CRF在应激诱导的乙醇消耗中的作用尚未研究。因此，这些实验将扩大目前的文献中的CRF在乙醇相关的表型小鼠的作用，从而帮助开发临床和药理学治疗的特点是过度饮酒的疾病。

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.