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）：酗酒和戒酒的复发是全球主要的健康问题，目前正在研究这些疾病的潜在药物治疗方法。但是，非依赖人的大量饮酒和暴饮暴食的关注要少得多。美国国家酒精滥用和酒精中毒研究所（NIAAA）定义了“暴饮暴食”，是一种饮酒模式，可在短时间内产生大于0.08％（80 mg/dl）的血液乙醇浓度（BEC）。非常关注的是，定期的暴饮暴食显着增加了患有乙醇依赖性的风险。因此，识别大脑中的神经化学途径调节暴饮暴食作为这种知识将提供对新型药物治疗的洞察，从而保护这种危险行为至关重要。我们已经发现，中央杏仁核（CEA）（CEA）的暴饮暴食会增加皮质激素释放因子（CRF）免疫反应性（IR），并且当注射到CEA中时，可以防止过度的暴饮暴食者（CRF1R）拮抗剂。喜欢在C57BL/6J小鼠中喝酒。另一方面，CRF1R拮抗剂无法改变中度的非诱形乙醇摄入量。这些观察结果平行的证据表明，CRF1R拮抗剂钝性依赖性饮酒，而不会改变非依赖性动物的乙醇摄入量。该赠款的指导假设是，急性暴饮暴食乙醇饮酒会在CEA中暂时参与CRF信号，以及在CEA引起的CRF途径所支配的位置，并且驱动器持续过多的乙醇摄入量。我们进一步假设，随着反复的暴饮暴食性发作，CRF信号的增加无法“正常化”，最终导致饮酒的持续增加。拟议的目标将使用强大而创新的电生理，组织学，遗传和行为技术来确定是否： b）CRF1R拮抗剂和CRF2R激动剂会在注射CEA（AIM 2）和C）抑制CEA中CRF产生CRF的神经元的CEA神经（AIM 2）和/或具有由设计师药物（Dreadds）激活的设计器受体（Dreadds）的Stria末端（BNST）的床核将防止类似暴饮暴食的乙醇饮用，而Dreadd诱导的CRF产生的神经元在这些地区的激活将增加暴饮暴食的饮酒（目标3）。这些高度创新的项目将通过深入了解过度暴饮暴食的乙醇饮用以及向类似依赖状态的过渡，并建立研究神经电路的新技术，从而提供临床前酒精中毒研究的转变。这可以调节过度的乙醇摄入量。