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

项目主任/首席研究员（最后、第一、中间）： 酗酒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。负面情绪状态，例如创伤后 应激障碍 (PTSD) 或焦虑症，受遗传因素影响或由环境条件决定 为塑造这一转变做出贡献。另一方面，长期接触酒精是一个主要决定因素。 情绪障碍（例如焦虑、抑郁、创伤后应激障碍（PTSD））和消极情绪状态（例如， 烦躁、烦躁）。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，以及压力的作用 这种大脑结构中的肽促肾上腺皮质激素释放因子（CRF）对于酒精的形成至关重要 依赖性和情绪障碍/负面影响。在上一个资助期间，我们提供了必要的 对 CRF1 受体系统先天过度表达与压力之间关系的新见解 基因选择的马尔基吉亚撒丁岛 (msP) 过敏和过量乙醇消耗 老鼠。我们最新的结果表明，msP 大鼠中 CRF 信号传导的增强是导致 脂肪酸酰胺水解酶（FAAH）的水解活性和内源性大麻素（ECB）信号减弱 CeA/BLA，导致杏仁核中 GABA 和谷氨酸的传输增强。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 mP 大鼠，这可能会增加饮酒以缓解这些负面状况。了解 通过先天和环境因素作用/相互作用来调节 CRF/eCB 的机制 BLA 和 CeA 中的传播将为酒精中毒的病因病理学提供新的见解，帮助 针对这种尚未得到治疗的疾病开发新疗法。本次研究计划 竞争性更新的目的是研究先天性（在 mP 大鼠）或 EtOH 诱导的（后依赖性 Wistars）CRF1 系统的上调有助于 过量饮酒并加剧适应不良的条件性恐惧反应，类似于症状 人类的创伤后应激障碍（PTSD）。通过 FAAH 抑制恢复正常 eCB 功能的能力，从而 抵消过度饮酒和使恐惧反应正常化，也将被研究。更好地理解 与远交 Wistar 大鼠相比，msP 基因型差异的分子机制 暴露于酒精后的神经适应，将为了解先天的易感性提供新的见解 开发酒精使用障碍，并将有助于开发新的治疗药物 缓解酒精依赖。 相关性（参见说明）：马尔基吉亚撒丁岛嗜酒 (msP) 大鼠代表了一种独特的大鼠 模型中，对高酒精偏好的遗传选择导致了高酒精度的共分离 对压力和焦虑的敏感性。该项目的目标是提供系统的调查 这些遗传因素和生物因素的影响在分子、神经化学和行为水平上 焦虑和饮酒行为的病因学机制。这些研究可能有助于确定 开发酒精中毒药物治疗的生物学目标以及常见的联合治疗 发生焦虑相关的疾病，例如创伤后应激障碍（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).