The role of corticotropin releasing factor in binge-like ethanol drinking

描述（由申请人提供）：戒酒者的酒精中毒和复发是世界范围内的主要健康问题，目前正在进行研究以确定这些疾病的潜在药物治疗方法。然而，非依赖性个体的大量饮酒和酗酒却很少受到关注。美国国家酒精滥用和酒精中毒研究所（NIAAA）将“狂饮”定义为在短时间内产生血液乙醇浓度（BECs）超过0.08%（80毫克/分升）的一种饮酒模式。值得关注的是，经常酗酒会显著增加对乙醇依赖的风险。因此，确定大脑中调节酗酒的神经化学途径至关重要，因为这些知识将为新的药物治疗提供见解，以防止这种危险行为。我们发现，酗酒样的乙醇饮酒增加了中央杏仁核（CeA）的促肾上腺皮质激素释放因子（CRF）免疫反应性（IR），并且当将1型受体（CRF1R）拮抗剂注射到CeA中时，可以防止C57BL/6J小鼠过度酗酒样饮酒。另一方面，CRF1R拮抗剂不能改变适度的非狂饮样乙醇摄入。这些观察结果与CRF1R拮抗剂在不改变非依赖动物的乙醇摄入量的情况下减弱依赖样饮酒的证据相一致。本研究的指导假设是，急性酗酒样的乙醇饮酒短暂地激活了CeA中的CRF信号，以及由CeA产生的CRF通路所支配的部位，并驱动了持续的过量乙醇摄入。我们进一步假设，增加的CRF信号不能“正常化”，反复的酗酒事件，最终导致饮酒持续增加。拟议的Aims将使用强大和创新的电生理，组织学，遗传学和行为学技术来确定是否：A)反复酗酒发作的历史将与CRF和CRF受体水平和功能的变化相关（目的1），B) CRF1R拮抗剂和CRF2R激动剂在注射到CeA和接受来自CeA的CRF神经支配的区域时将保护免受酗酒样乙醇饮酒（目的2）。C)在CeA和/或终纹（BNST）的床核中，用专门被设计药物（dreadd）激活的设计受体抑制产生crf的神经元，将防止酗酒样饮酒，而在这些区域，由设计药物（dreadd）诱导的产生crf的神经元的激活将增加酗酒样饮酒（目的3）。这些高度创新的项目将通过深入了解CRF1R和CRF2R信号在过量酒精类饮酒和向依赖状态过渡中的作用，为临床前酒精中毒研究提供转变，并为研究调节过量酒精摄入的神经回路建立新技术。

DESCRIPTION (provided by applicant): Alcoholism and relapse in abstinent alcoholics are major health problems world-wide and current research is underway to identify potential pharmaceutical treatments for these disorders. However, heavy alcohol use and binge alcohol drinking by non-dependent individuals have received far less attention. A 'binge' is defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as a pattern of drinking that produces blood ethanol concentrations (BECs) greater than 0.08% (80 mg/dL) within a short period of time. Of great concern, regular binge drinking significantly increases ones risk of developing ethanol dependence. Thus, it is of paramount importance to identify neurochemical pathways in the brain that modulate binge drinking as such knowledge will provide insight into novel pharmaceutical treatments that will protect against this dangerous behavior. We have found that binge-like ethanol drinking increases corticotropin releasing factor (CRF) immunoreactivity (IR) in the central amygdala (CeA) and that a type-1 receptor (CRF1R) antagonist, when injected into the CeA, protects against excessive binge-like drinking in C57BL/6J mice. On the other hand, CRF1R antagonists fail to alter moderate non-binge-like ethanol intake. These observations parallel evidence that CRF1R antagonists blunt dependence-like drinking without altering ethanol intake in non-dependent animals. The guiding hypothesis for this grant is that acute binge-like ethanol drinking transiently engages CRF signaling in the CeA, and at sites that are innervated by CRF pathways arising from the CeA, and drives continued excessive ethanol intake. We further hypothesize that increased CRF signaling fails to "normalize" with repeated binge-like drinking episodes, ultimately contributing to persistent increases in alcohol drinking. The proposed Aims will use powerful and innovative electrophysiological, histological, genetic, and behavioral techniques to determine if: A) A history of repeated binge-like drinking episodes will be associated with changes in CRF and CRF receptor levels and function (Aim 1), B) CRF1R antagonist and a CRF2R agonist will protect against binge-like ethanol drinking when injected into the CeA and regions that receive CRF innervation from the CeA (Aim 2), and C) inhibition of CRF-producing neurons in the CeA and/or bed nucleus of the stria terminalis (BNST) with designer receptors that are exclusively activated by designer drugs (DREADDs) will protect against binge-like ethanol drinking, and DREADD-induced activation of CRF-producing neurons in these regions will increase binge-like drinking (Aim 3). These highly innovative projects will provide a shift in pre-clinical alcoholism research by providing insight into the role for CRF1R and CRF2R signaling in excessive binge-like ethanol drinking and the transition to a dependence-like state, and establish new technologies for studying the neurocircuitry that modulates excessive ethanol intake.