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: 9274895
• 负责人: TODD E. THIELE
• 金额: $ 29.6万
• 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9274895
• 关键词: Acute; Address; Agonist; Alcohol consumption; Alcohol dependence; Alcoholism; Amygdaloid structure; Animals; Attention; Behavioral; Blood; Brain; Clozapine; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Dangerous Behavior; Dependence; Development; Disease; Electrophysiology (science); Ethanol; Ethanol dependence; G alpha q Protein; Genetic; Grant; Health; Heart Diseases; Heavy Drinking; Histologic; Hour; Hypertension; Individual; Infusion procedures; Injectable; Injection of therapeutic agent; Knowledge; Link; Messenger RNA; Modeling; Mood Disorders; Mus; National Institute on Alcohol Abuse and Alcoholism; Neuronal Plasticity; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Oxides; Pathway interactions; Pattern; Pharmacologic Substance; Preparation; Procedures; Proteins; Recombinant adeno-associated virus (rAAV); 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; designer receptors exclusively activated by designer drugs; 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)：戒酒和戒酒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，非依赖型个人的酗酒和酗酒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“酗酒”定义为在短时间内产生血液酒精浓度(BEC)超过0.08%(80毫克/分升)的饮酒模式。非常令人担忧的是，经常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路径至关重要，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洞察。我们发现，酗酒样饮酒增加了中央杏仁核(CEA)促肾上腺皮质激素释放因子(CRF)免疫反应性(IR)，当向CEA注射1型受体(CRF1R)拮抗剂时，可以保护C57BL/6J小鼠免受过度酗酒。另一方面，CRF1R拮抗剂无法改变适度的非暴饮式乙醇摄入量。这些观察与CRF1R拮抗剂同时存在的证据表明，CRF1R拮抗剂在不改变非依赖动物的酒精摄入量的情况下，减弱了依赖类饮酒的作用。这项资助的指导性假说是，急性暴饮式酒精饮酒在CEA和由CEA产生的CRF通路神经支配的部位瞬时参与CRF信号传递，并推动持续过量的酒精摄入。我们进一步假设，CRF信号的增加未能在反复暴饮式饮酒发作中“正常化”，最终导致饮酒持续增加。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：A)反复暴饮性饮酒发作的病史是否与CRF和CRF受体水平和功能的变化有关(目标1)，B)CRF1R拮抗剂和CRF2R激动剂在注射到CEA和从CEA接受CRF神经支配的区域时是否可以防止酗酒(目标2)，以及C)用设计受体(DREADD)专属激活的设计受体(DREADD)抑制CEA和/或终纹床核(BNST)中产生CRF的神经元是否可以防止酗酒，乙醇DREADD诱导的这些区域产生CRF的神经元的激活将增加暴饮式饮酒(目标3)。这些高度创新的项目将通过深入了解CRF1R和CRF2R信号在过量饮酒和向依赖状态转变中的作用，提供临床前酒精中毒研究的转变，并建立研究调节过度酒精摄入的神经电路的新技术。