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

项目总监/首席调查员(最后、第一、中间)： 酒精中毒是一种慢性复发性障碍，随着时间的推移而发展，其特征是过渡 从娱乐饮酒到滥用和依赖。负面情绪状态，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 为塑造这一过渡做出贡献。另一方面，长期接触酒精是一个主要决定因素。 对于情绪紊乱(例如，焦虑、抑郁、创伤后应激障碍)和负面情绪状态(即， 烦躁不安、易怒)。杏仁核[杏仁中央核(CEA)和 杏仁基底外侧核(BLA)]被认为是负性情绪回路的中枢，而压力的作用 这种大脑结构中的促肾上腺皮质激素释放因子(CRF)对酒精的形成至关重要 依赖性和情绪障碍/负面情绪。在上一个资助期内，我们提供了必要的 CRF1受体系统先天过度表达与应激关系的新认识 遗传选择的Marchigian Sardian(MSP)的超敏反应和过量酒精消耗 老鼠。我们最新的结果表明，MSP大鼠CRF信号的增强是导致 脂肪酸酰胺水解酶(FAAH)和钝化内源性大麻素(ECB)信号的水解性 CEA/BLA，导致杏仁核内GABA和谷氨酸传递增强。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，这可能会增加饮酒量，以缓解这些负面条件。了解 先天因素和环境因素共同作用/相互作用机制失调CRF/ECB BLA和CEA的传递将为酒精中毒的病因提供新的见解，有助于 为这种在很大程度上仍未得到治疗的疾病开发新的治疗方法。这方面的研究计划 竞争性更新是研究先天(In)如何触发杏仁核内ECB信号的改变 MSP大鼠)或乙醇诱导的(依赖后的Wistars)CRF1系统上调有助于 过量饮酒会加剧与症状类似的适应不良的条件性恐惧反应 人类的创伤后应激障碍。通过抑制FAAH恢复正常ECB功能的能力，从而 对抗过度饮酒和正常化恐惧反应，也将被研究。更好地理解 MSP与近交系Wistar和Wistar大鼠基因差异的分子机制 对暴露于酒精后的神经适应的研究，将为我们提供关于先天易感性的新见解 发展酒精使用障碍，将有助于开发新的治疗药物 减轻酒精依赖。 相关性(见说明)：Marchigian撒丁岛嗜酒(MSP)大鼠代表着一种独特的大鼠 对高酒精偏好的遗传选择导致共分离的模型 对压力和焦虑敏感。该项目的目标是在 分子、神经化学和行为水平对这些遗传因素和生物学的影响 焦虑和饮酒行为的病因学机制。这些研究可能有助于确定 发展酒精中毒药物治疗的生物学靶点和频繁的联合治疗 出现焦虑相关障碍，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).