Gene-environment interaction: the brain CRF system in alcohol preferring msP rats

项目负责人/主要研究者（最后一名、第一名、中间名）： 酒精中毒是一种慢性复发性疾病，随着时间的推移而发展，其特点是过渡 从娱乐性饮酒到滥用和依赖。消极的情绪状态，如创伤后 应激障碍（PTSD）或焦虑，受遗传因素影响或由环境条件决定 有助于塑造这种转变。另一方面，长期接触酒精是一个主要的决定因素， 对于情绪障碍的发生（例如，焦虑、抑郁、创伤后应激障碍）和负面情绪状态（即， 烦躁、易怒）。杏仁核[杏仁核中央核（CeA）和 基底外侧杏仁核（BLA）被认为是负面情绪回路的枢纽，压力的作用 在这个大脑结构中，促肾上腺皮质激素释放因子（CRF）肽对酒精的产生和 依赖和情绪障碍/负面影响。在上一个融资期，我们提供了必要的 对CRF 1受体系统先天性过度表达、应激 遗传选择Marchigian Sardinian（msP）超敏反应和过量乙醇消耗 大鼠我们最近的研究结果表明，在msP大鼠中增强的CRF信号传导是导致增加的 脂肪酸酰胺水解酶（FAAH）的水解活性和钝的内源性大麻素（eCB）信号传导在 CeA/BLA，导致杏仁核中GABA和谷氨酸传输增强。我们的假设是 这种改变有助于增强应激敏感性，并加剧焦虑样症状， msP大鼠，这可能会增加饮酒，以减轻这些负面条件。了解 通过与先天和环境因素作用/相互作用的机制，使CRF/eCB失调 BLA和CeA的传播将为酒精中毒的病因学提供新的见解， 开发新的治疗方法来治疗这种仍在很大程度上未经治疗的疾病。对此的研究计划 竞争性更新的目的是研究杏仁核中的eCB信号是如何被先天性（ msP大鼠）或EtOH诱导的（后依赖性Wistars）CRF 1系统上调有助于 过度饮酒和加剧适应不良的条件性恐惧反应，类似于症状 创伤后应激障碍通过FAAH抑制恢复正常eCB功能的能力， 抵消过量饮酒和正常化的恐惧反应，也将进行研究。更好地了解 与远交Wistar大鼠相比，msP基因型差异的分子机制， 神经适应暴露于酒精后，将提供新的见解先天易感性， 开发酒精使用障碍，并将有助于开发新的治疗药物， 减轻酒精依赖。 相关性（参见说明）：Marchigian Sardinian酒精偏好（msP）大鼠代表了一种独特的大鼠 一个模型，在该模型中，对高度酒精偏好的遗传选择导致了升高的 对压力和焦虑的敏感性。该项目的目标是提供一个系统的调查， 分子、神经化学和行为水平的影响，这些遗传因素和生物 焦虑和饮酒行为的病因学机制。这些研究可能有助于识别 酒精中毒药物治疗发展的生物学靶点，以及常见的 发生焦虑相关的障碍，如创伤后应激障碍（PTSD）。

Program Director/Principal Investigator (Last, First, Middle): Alcoholism is a chronically relapsing disorder that develops over time and is characterized by the transition from recreational alcohol use to abuse and dependence. Negative emotional states, such as posttraumatic stress disorder (PTSD) or anxiety, influenced by genetic factors or determined by environmental conditions contribute to shaping this transition. On the other hand, chronic exposure to alcohol is a major determinant for the occurrence of mood disorders (e.g., anxiety, depression, PTSD) and negative emotional states (i.e., dysphoria, irritability). The amygdalar nuclei [both the central nucleus of the amygdala (CeA) and basolateral amygdala (BLA)] are considered a hub for negative emotional circuitry, and the role of the stress peptide corticotropin-releasing factor (CRF) in this brain structure is critical for both development of alcohol dependence and mood disorders/negative affect. During the previous funding period we provided essential new insight into the relationship between innate overexpression of the CRF1 receptor system, stress hypersensitivity and excessive ethanol consumption in genetically selected Marchigian Sardinian (msP) rats. Our most recent results show that enhanced CRF signaling in msP rats is responsible for increased hydrolytic activity of fatty acid amide hydrolase (FAAH) and blunted endocannabinoid (eCB) signaling in the CeA/BLA, leading to enhanced GABA and glutamate transmission in the amygdala. Our hypothesis is that such alterations contribute to enhance stress sensitivity and to exacerbate anxiety-like symptoms in the msP rats, which may increase drinking to alleviate these negative conditions. Understanding the mechanisms through with innate and environmental factors act/interact to dysregulate CRF/eCB transmission in the BLA and CeA will provide new insight into the etiopathology of alcoholism, aiding the development of new therapeutics for this still largely untreated medical condition. The research plan for this competitive renewal is to investigate how alteration of eCB signaling in the amygdala triggered by innate (in msP rats) or EtOH-induced (post-dependent Wistars) upregulation of the CRF1 system contributes to excessive alcohol drinking and exacerbates maladaptive conditioned fear responses, similar to symptoms of PTSD in humans. The ability to restore normal eCB function by FAAH inhibition, and therefore to counteract excessive drinking and normalize fear responses, will be also studied. A better understanding of the molecular mechanism underlying genotypic differences of the msP compared to outbred Wistar rats and of neuroadaptations following exposure to alcohol, will provide novel insight into the innate susceptibility to develop Alcohol Use Disorder and will be useful toward the development of new therapeutic agents to alleviate alcohol dependence. RELEVANCE (See instructions): The Marchigian Sardinian alcohol-preferring (msP) rats represent an unique rat model in which genetic selection for high alcohol preference has led to co-segregation of elevated sensitivity to stress and anxiety. The goal of this project is to provide a systematic investigation at the molecular, neurochemical and behavioral levels of the impact of these heritable factors and biological mechanisms in the etiology of anxiety and alcohol drinking behavior. These studies may help identify biological targets for the development of pharmacological treatment for alcoholism and the frequent co- occurrence anxiety related disorders, such as post-traumatic stress disorder (PTSD).