CRF regulation of BNST target control in alcohol withdrawal

CRF 调节 BNST 酒精戒断目标控制

• 批准号: 8320777
• 负责人: Yuval Silberman
• 金额: $ 5.39万
• 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/8320777
• 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）是一种慢性复发疾病，对个人健康以及美国的社会经济福祉产生了很大影响，估计每年在AUD相关问题上花费1840亿美元。因此，找到药物治疗靶标以减轻AUDS非常重要。最近的研究表明，过度食用酒精的最初动机可能依赖于大脑阳性增强系统的激活，这主要是由多巴胺（DA）从腹侧偏段释放介导的。在AUDS开发的某个时刻，人们认为过渡会发生，使得过度消耗酒精从依赖积极强化到负强化系统的动机。扩展的杏仁核是一个对介导焦虑和压力反应重要的大脑区域，以及据认为与压力反应性有关的神经递质释放因子（CRF）的皮质营养素释放因子（CRF），被认为与AUD开发所需的负强化途径相关。但是，尚不知道在AUDS开发过程中使用正和负增强系统之间的切换所涉及的确切性质和神经记录。 我们实验室的最新工作显示了正面和负强化系统之间的潜在直接联系，从而可以提高质末端（BNST）床核中的CRF水平，这是扩展的杏仁核的一个组成部分，通常被描述为正阳性和负强化途径中信息的中间管理器。长期以来，在包括BNST在内的许多大脑区域中，酒精暴露已被证明会增加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，在许多啮齿动物模型中，它进一步已被证明会增加焦虑样行为。此外，还显示出从酒精暴露中退出会增加BNST中的CRF水平并增加焦虑症。此外，已证明重复的CRF受体刺激会引起BNST调节的焦虑样行为的敏感性。因此，预计反复的酒精暴露和戒断会导致BNST的CRF水平增加，这是通过在酒精暴露期间通过DA进行的间接调节以及在退出期间直接增加CRF释放的。假设酒精DA与CRF之间的这种相互作用会引起BNST CRF受体的敏化，因此是AUD发育中正和负强化之间的初始过渡点。该建议将整合电生理，药理，行为和荧光成像技术，以确定在慢性间歇性酒精暴露和哪些BNST输出神经元受到这种敏化影响后，BNST CRF是否敏感。这些研究的成功完成可能揭示了对AUD发育的新见解，并可能揭示了对这种令人衰弱的疾病治疗的未来药理干预措施的新颖目标。 公共卫生相关性：酒精中毒是一种毁灭性且昂贵的疾病，该疾病是由于导致最初过量饮酒和后一种依赖性的神经通律过渡而发展的。一个潜在的过渡成分可能是质末端的床核中的独特途径，这是参与调节单独奖励和压力系统调节的大脑区域，这可能对长期酒精暴露和戒断的侮辱尤其敏感。该提案旨在检查这种独特的途径，并在反复的酒精暴露和提取后确定它如何改变，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。