CFR signaling in stress- and dependence- induced ethanol consumption

描述(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受体信号参与了乙醇依赖动物的过度自愿乙醇消耗，以及应激诱导的非依赖动物乙醇消耗的增加。事实上，最近的研究探索了针对CRF的药物的使用，将其作为与过度饮酒相关的疾病的潜在治疗方法。由于CRF信号似乎是酒精引起的神经生物学反应的基础，涉及应激暴露或依赖史，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)的显著神经适应。因此，这一建议的指导性假设是，与应激和酒精依赖相关的乙醇消耗的增加是通过CRF1和CRF2受体在杏仁核中通过CRF信号转导的。为了研究CRF1和CRF2信号在C57BL/6J小鼠依赖诱导的酒精消耗增加表达中的作用，CRF1受体拮抗剂CP-154,526将在外周和中央给药，CRF2受体激动剂将在暴露于多次乙醇蒸气和戒断后中央给药。为了研究杏仁核CRF在C57BL/6J小鼠依赖诱导的乙醇消耗量增加的获得/表达中的作用，将在暴露于多次乙醇蒸气和戒断以及有限的自由获得乙醇之前进行定位输注CRF-SAP。为了研究杏仁核CRF在BALB/CJ小鼠应激诱导的乙醇消耗量增加的获得/表达中的作用，将在暴露于强迫游泳应激和持续自由接触乙醇之前进行CRF-SAP的定位输注。CRF信号的作用，通过CRF1和CRF2受体，以及杏仁核CRF信号将通过这些实验进一步评估。虽然有一些证据表明CRF信号与依赖诱导的小鼠酒精消耗有关，但到目前为止，只有少数已发表的报告研究CRF1R的作用，据我们所知，没有发表报告研究CRF2R在有酒精依赖史的小鼠中的作用。此外，到目前为止，杏仁核CRF在应激诱导的酒精消耗中的作用还没有被研究。因此，这些实验将把目前关于CRF在酒精相关表型中的作用的文献扩展到小鼠，从而帮助开发以过量酒精摄入为特征的疾病的临床和药理学治疗方法。

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.