The role of medial prefrontal cortex CRF signaling in binge-like ethanol intake

内侧前额叶皮质 CRF 信号在暴饮暴食乙醇摄入中的作用

基本信息

批准号：
9396186
负责人：
Stacey Robinson
金额：
$ 5.71万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9396186
关键词：
Address Alcohol abuse Alcohol consumption Alcohol dependence Alcoholism Alcohols Amygdaloid structure Animals Anxiety Attention Behavior Bilateral Biochemical Blood Brain CRF receptor type 1 CRH gene Cannulations Clozapine Consumption Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Coupled Dangerousness Darkness Development Diabetes Mellitus Emotional Ethanol Ethanol dependence Expenditure Female Goals Health Healthcare Heart Diseases Heavy Drinking Human Immunohistochemistry Injection of therapeutic agent Internal Ribosome Entry Site Investigation Lead Link Literature Lobotomies Maintenance Medial Mediating Microinjections Modeling Mus National Institute on Alcohol Abuse and Alcoholism National Research Service Awards Neurobiology Neurons Neuropeptides Oxides Pattern Pharmacogenetics Pharmacology Play Prefrontal Cortex Public Health Research Research Training Rewards Risk Factors Rodent Role Signal Transduction Site Stress System Technical Expertise Techniques Technology Testing Time Transgenic Mice Transgenic Organisms United States Viral Viral Vector Water Western Blotting Withdrawal Work alcohol abuse therapy alcohol behavior alcohol exposure alcohol response alcohol seeking behavior behavioral pharmacology binge drinking career corticotropin releasing factor-binding protein cost design designer receptors exclusively activated by designer drugs drinking drinking behavior executive function experimental study frontal lobe insight interest male mouse model neglect neural circuit neuromechanism receptor response therapeutic target

项目摘要

Project Summary/Abstract Alcohol dependence is a widespread public health concern with limited treatment options available. A growing body of evidence supports binge intake of ethanol as a significant risk factor for the development of ethanol dependence. Additionally, this form of excessive ethanol intake is associated with negative health effects, such as heart disease and diabetes, and represents a significant portion of the financial burden induced by alcohol use within the United States. Our lab and others have extensively demonstrated the neuropeptide corticotropin releasing factor (CRF) plays an important role in modulating binge ethanol consumption. Further, alterations in the CRF system are known to play an important role in ethanol-related behaviors both following the development of ethanol-dependence and into withdrawal. Dissecting the specific role of CRF in binge drinking behavior in non-ethanol dependent animals therefore enables the discovery of treatments for this risky pattern of behavior and, further, provides important insights into initial ethanol related alterations of a system critically involved in the development and maintenance of ethanol-dependence. The role of CRF in ethanol-related behaviors within the extended amygdala has been the focus of numerous investigations. However, the role of CRF within regions critical to entraining these limbic regions and coordinating reward-directed/inhibiting inappropriate behaviors has gone essentially neglected. This proposal focuses on addressing this hole in the literature by examining the role of CRF within the medial prefrontal cortex (mPFC) in modulating binge ethanol consumption. The proposed studies will employ biochemical, pharmacogenetic, transgenic, and behavioral pharmacological approaches. The well-validated model of binge-like ethanol intake in rodents ‘drinking in the dark’ (DID) will be used throughout these experiments. For Aim 1, I will use the DID paradigm and immunohistochemistry and western blot techniques to assess whether 1 or 3-weeks of DID alter components of the mPFC CRF system (CRF, CRF receptor 1 and 2 (CRF1R/CRF2R), CRF-binding protein). For Aim 2, I will use designer receptor technology (viral injection of Cre-dependent DREADDs) along with CRH-IRES-Cre transgenic mice in the DID model to (1) determine whether ‘silencing’ CRF neurons (via activation of inhibitory DREADDs) in the mPFC decreases binge-like ethanol intake and associated blood ethanol concentrations (BECs) and (2) assess whether activation of CRF neurons (via excitatory DREADDs) in the in the mPFC decreases binge-like ethanol intake and associated BECs. For Aim 3, I will use behavioral pharmacology and site-specific microinjections to assess the relative contribution of the CRF1R and CRF2R receptors within the mPFC in modulating binge-like ethanol intake in the DID paradigm. Results from this project will advance our understanding of the neural mechanisms underlying binge-like ethanol intake, as well as characterize the potential for specific components of the mPFC CRF system to serve as a therapeutic target for treatment of alcohol dependence.

项目概要/摘要酒精依赖是一个普遍的公共卫生问题，可用的治疗选择越来越有限。大量证据支持暴饮暴食乙醇是形成乙醇的一个重要风险因素此外，这种形式的过量乙醇摄入还会对健康产生负面影响，例如。如心脏病和糖尿病，并且占酒精引起的经济负担的很大一部分我们的实验室和其他实验室主要证明了神经肽促肾上腺皮质激素的使用。释放因子（CRF）在调节暴饮暴食乙醇消耗方面发挥着重要作用。众所周知，CRF 系统在乙醇相关行为中发挥着重要作用，既遵循发展酒精依赖和戒断 CRF 在酗酒行为中的具体作用。因此，非乙醇依赖动物能够发现这种危险行为模式的治疗方法并且进一步提供了对关键参与系统的初始乙醇相关改变的重要见解 CRF 在乙醇相关行为中的作用。扩展的杏仁核一直是众多研究的焦点，然而，CRF 在区域内的作用。引导这些边缘系统并协调奖励导向/抑制不当行为的关键区域该提案的重点是通过检查来解决文献中的这一漏洞。内侧前额叶皮质 (mPFC) 内的 CRF 在调节酗酒乙醇消耗中的作用。拟议的研究将采用生物化学、药物遗传学、转基因和行为药理学啮齿类动物“在黑暗中饮酒”（DID）的暴食乙醇摄入模型已得到充分验证。对于目标 1，我将使用 DID 范式和免疫组织化学，并且蛋白质印迹技术评估 1 或 3 周的 DID 是否改变 mPFC CRF 系统的组成部分（CRF、CRF 受体 1 和 2 (CRF1R/CRF2R)、CRF 结合蛋白）对于目标 2，我将使用设计受体。技术（病毒注射 Cre 依赖性 DREADD）以及 DID 中的 CRH-IRES-Cre 转基因小鼠模型 (1) 确定是否“沉默”mPFC 中的 CRF 神经元（通过激活抑制性 DREADD）减少暴饮暴食型乙醇摄入量和相关的血液乙醇浓度 (BEC)，并且 (2) 评估是否 mPFC 中 CRF 神经元的激活（通过兴奋性 DREADD）可减少暴饮暴食型乙醇摄入量对于目标 3，我将使用行为药理学和定点显微注射来评估。 mPFC 内 CRF1R 和 CRF2R 受体在调节狂饮型乙醇中的相对贡献该项目的结果将促进我们对神经机制的理解。潜在的暴饮暴食乙醇摄入量，以及表征 mPFC 特定组件的潜力 CRF系统作为治疗酒精依赖的治疗靶点。