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

促肾上腺皮质激素释放因子在酗酒中的作用

• 批准号: 8700253
• 负责人: TODD E. THIELE
• 金额: $ 28.71万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700253
• 关键词: Acute; Address; Agonist; Alcohol consumption; Alcohol dependence; Alcoholism; Amygdaloid structure; Animals; Attention; Behavioral Genetics; Blood; Brain; Clozapine; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Dangerous Behavior; Dependence; Designer Drugs; Development; Disease; Ethanol; Ethanol dependence; G alpha q Protein; Grant; Health; Heart Diseases; Heavy Drinking; Hour; Hypertension; Individual; Infusion procedures; Injection of therapeutic agent; Knowledge; Link; Messenger RNA; Modeling; Mood Disorders; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Oxides; Pathway interactions; Pattern; Pharmacologic Substance; Preparation; Procedures; Proteins; Recording of previous events; Relapse; Research; Risk; Role; Signal Transduction; Site; Slice; Structure of terminal stria nuclei of preoptic region; Techniques; Testing; Time; Ventral Tegmental Area; Whole-Cell Recordings; binge drinking; desensitization; drinking; immunoreactivity; innovation; insight; nerve supply; neurochemistry; new technology; novel; pre-clinical; prevent; problem drinker; public health relevance; receptor; response; stem; transmission process

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.

描述（由申请人提供）：酒精中毒和戒酒者的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。然而，非依赖性个人的重度饮酒和酗酒问题受到的关注要少得多。美国国家酒精滥用和酒精中毒研究所（NIAAA）将“狂欢”定义为在短时间内产生血液乙醇浓度（BEC）大于0.08%（80 mg/dL）的饮酒模式。值得关注的是，经常性的酗酒会显著增加人们对酒精依赖的风险。因此，确定大脑中调节酗酒的神经化学途径至关重要，因为这些知识将为预防这种危险行为的新型药物治疗提供见解。我们已经发现，酗酒样乙醇饮酒增加促肾上腺皮质激素释放因子（CRF）的免疫反应性（IR）在中央杏仁核（CeA）和1型受体（CRF 1 R）拮抗剂，当注射到CeA，防止过度酗酒样饮酒C57 BL/6 J小鼠。另一方面，CRF 1 R拮抗剂未能改变中度非狂欢样乙醇摄入。这些观察结果平行的证据表明，CRF 1 R拮抗剂钝的依赖性，如饮酒，而不改变非依赖性动物的乙醇摄入量。这项研究的指导性假设是，急性酗酒样乙醇饮用短暂地参与了CeA中的CRF信号传导，并在由CeA引起的CRF通路支配的部位，并驱动持续过量的乙醇摄入。我们进一步假设，增加CRF信号未能“正常化”与反复狂饮样饮酒事件，最终导致持续增加饮酒。拟议的目标将使用强大和创新的电生理学，组织学，遗传学和行为技术来确定是否：A）反复暴饮暴食的饮酒史将与CRF和CRF受体水平和功能的变化相关（目的1），B）CRF 1 R拮抗剂和CRF 2 R激动剂将保护免于暴食-就像酒精饮料一样，当注射到CeA和接受来自CeA的CRF神经支配的区域时（目标2），和C）用专门被设计药物激活的设计受体（DREADD）抑制CeA和/或终纹床核（BNST）中的CRF产生神经元将防止酗酒样乙醇饮酒，DREADD诱导的这些区域中产生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CRF 1 R和CRF 2 R信号在过度酗酒样乙醇饮酒和向依赖样状态过渡中的作用，为临床前酗酒研究带来转变，并建立新技术来研究调节过量乙醇摄入的神经回路。