CRF regulation of BNST target control in alcohol withdrawal

CRF 调节 BNST 酒精戒断目标控制

• 批准号: 8059909
• 负责人: Yuval Silberman
• 金额: $ 4.76万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059909
• 关键词: Address; Affect; Agonist; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcoholism; Alcohols; American; Amygdaloid structure; Anxiety; Behavior; Behavioral; Brain; Brain region; Chronic; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Dependence; Dependency; Development; Disease; Dopamine; Feeling; Future; Glutamates; Goals; Health; Hypothalamic structure; Imaging Techniques; Individual; Intervention; Lead; Mediating; Motivation; Mus; Nature; Negative Reinforcements; Neuraxis; Neurobiology; Neurologic; Neurons; Neurotransmitters; Output; Pathway interactions; Personal Satisfaction; Pituitary Gland; Population; Positive Reinforcements; Probability; Process; Recurrent disease; Regulation; Relapse; Reliance; Research; Rewards; Rodent Model; Signal Transduction; Staging; Stress; Structure of terminal stria nuclei of preoptic region; Synapses; Synaptic Transmission; System; Techniques; Testing; Tracer; United States; Ventral Tegmental Area; Withdrawal; Work; alcohol exposure; alcohol use disorder; alcoholism therapy; biological adaptation to stress; dopaminergic neuron; drinking; drinking behavior; economic cost; insight; negative emotional state; novel; paraventricular nucleus; public health relevance; research study; socioeconomics; stressor; theories; transmission process; vapor

DESCRIPTION (provided by applicant): Alcohol use disorder (AUD) is a chronic relapsing disease that has a great impact on individual health as well as the socio-economic well-being of the US as an estimated $184 billion dollars are spent annually on AUD related problems. Therefore, finding pharmacotherapeutic targets to alleviate AUDs is of great importance. Recent research shows that the initial motivation to excessively consume alcohol may be reliant upon activation of the brain's positive reinforcement system which is predominantly mediated by dopamine (DA) release from the ventral tegmental area. At some point in the development of AUDs a transition is thought to occur such that motivation to excessively consume alcohol switches from reliance on positive reinforcement to negative reinforcement systems. The extended amygdala, a brain region important in mediating anxiety and stress responses, and corticotrophin releasing factor (CRF), a neurotransmitter thought to be involved in stress reactivity, are thought to be heavily involved in the negative reinforcement pathways required for AUD development. However, the exact nature and neurocircuitry involved in the switch between utilizing positive and negative reinforcement systems during the development of AUDs is not yet known. Recent work from our lab has shown a potentially direct connection between positive and negative reinforcement systems whereby DA can elevate CRF levels in the bed nucleus of the stria terminalis (BNST), a component of the extended amygdala that is often described as a middle manager of information in both the positive and negative reinforcement pathways. Alcohol exposure has long been shown to increase DA levels in many brain regions, including the BNST, which suggests that alcohol exposure would also increase BNST CRF levels. CRF has been shown to increase the excitability of BNST neurons, which has further been shown to increase anxiety-like behaviors in many rodent models. In addition, withdrawal from alcohol exposure has also been shown to increase CRF levels in the BNST and increase anxiety. Furthermore, repeated CRF receptor stimulation has been shown to cause a sensitization of anxiety-like behaviors regulated by the BNST. Therefore, repeated alcohol exposures and withdrawals would be expected to cause increased levels of CRF in the BNST, both via indirect modulation via DA during alcohol exposure and by directly increasing CRF release during withdrawal. This interaction between alcohol DA and CRF is hypothesized to cause a sensitization of BNST CRF receptors and therefore be the initial transition point between positive and negative reinforcement in AUD development. This proposal will integrate electrophysiological, pharmacological, behavioral, and fluorescent imaging techniques to determine if BNST CRF sensitize following chronic intermittent alcohol exposure and which BNST output neurons are affected by this sensitization. Successful completion of these studies may reveal new insights into AUD development and possibly uncover novel targets for future pharmacological interventions in the treatment of this debilitating disease. PUBLIC HEALTH RELEVANCE: Alcoholism is a devastating and costly disease hypothesized to develop due a transition in the neurocircuitry responsible for initial excessive alcohol drinking and latter dependency. One potential transitional component may be a unique pathway in the bed nucleus of the stria terminalis, a brain region involved in the regulation of the separate reward and stress systems, which may be especially sensitive to insults by chronic alcohol exposures and withdrawals. This proposal aims to examine this unique pathway and determine how it may change following repeated alcohol exposures and withdrawals with the goal of revealing novel targets for the development of new and better treatments for alcoholism.

描述（由申请人提供）：酒精使用障碍 (AUD) 是一种慢性复发性疾病，对个人健康以及美国的社会经济福祉具有重大影响，因为每年估计有 1,840 亿美元用于与 AUD 相关的问题。因此，寻找缓解AUD的药物治疗靶点非常重要。最近的研究表明，过度饮酒的最初动机可能依赖于大脑正强化系统的激活，该系统主要由腹侧被盖区释放的多巴胺（DA）介导。在 AUD 发展的某个时刻，人们认为会发生一种转变，过度饮酒的动机从依赖正强化系统转变为依赖负强化系统。扩展的杏仁核是调节焦虑和压力反应的重要大脑区域，而促肾上腺皮质激素释放因子（CRF）是一种被认为与压力反应有关的神经递质，被认为与 AUD 发展所需的负强化途径密切相关。然而，在 AUD 的发展过程中，利用正强化系统和负强化系统之间的转换所涉及的确切性质和神经回路尚不清楚。 我们实验室最近的工作表明，正强化和负强化系统之间存在潜在的直接联系，DA 可以提高终纹床核 (BNST) 中的 CRF 水平，BNST 是扩展杏仁核的一个组成部分，通常被描述为正强化和负强化路径中信息的中间管理者。长期以来，酒精暴露已被证明会增加许多大脑区域（包括 BNST）的 DA 水平，这表明酒精暴露也会增加 BNST CRF 水平。 CRF 已被证明可以增加 BNST 神经元的兴奋性，这在许多啮齿动物模型中进一步被证明可以增加焦虑样行为。此外，戒酒也被证明会增加 BNST 中的 CRF 水平并增加焦虑。此外，重复的 CRF 受体刺激已被证明会引起由 BNST 调节的焦虑样行为的敏感性。因此，反复的酒精暴露和戒断预计会导致 BNST 中 CRF 水平增加，这既是通过酒精暴露期间通过 DA 进行间接调节，又是通过在戒断期间直接增加 CRF 释放。据推测，酒精 DA 和 CRF 之间的这种相互作用会引起 BNST CRF 受体的敏化，因此是 AUD 发展中正强化和负强化之间的初始过渡点。该提案将整合电生理学、药理学、行为和荧光成像技术，以确定 BNST CRF 是否在慢性间歇性酒精暴露后敏化，以及哪些 BNST 输出神经元受到这种敏化的影响。这些研究的成功完成可能会揭示对 AUD 发展的新见解，并可能为未来治疗这种使人衰弱的疾病的药物干预措施发现新的目标。 公共卫生相关性：酗酒是一种破坏性且代价高昂的疾病，据推测是由于神经回路的转变导致最初的过量饮酒和后来的依赖。一个潜在的过渡成分可能是终纹床核中的独特通路，终纹是一个参与调节奖励和压力系统的大脑区域，可能对慢性酒精暴露和戒断造成的损害特别敏感。该提案旨在研究这一独特的途径，并确定其在反复接触酒精和戒酒后如何变化，目的是揭示新的目标，以开发新的、更好的酒精中毒治疗方法。