Neuropharmacology of Ethanol Reinforcement

描述（由申请人提供）：酒精中毒是一种慢性复发性疾病，其特征为寻求和服用酒精的强迫性，并与大脑唤醒和情绪系统的失调有关，这些系统关键性地参与了对酒精中毒发展至关重要的积极和消极强化。依赖性和复发的脆弱性被认为包括大脑情绪系统中的反适应性神经化学事件，这些情绪系统通常用于维持情绪稳态（Koob和Le Moal，2005，2008，附录）并通过负强化机制产生强迫性饮酒。在上一个资助期，我们的特点是大脑应激系统促肾上腺皮质激素释放因子（CRF）和去甲肾上腺素的活性增加，神经肽Y抗应激系统的活性降低，在依赖性诱导的饮酒的关键作用。本竞争性更新的研究计划将继续研究依赖性诱导的过量饮酒发展过程中脑唤醒应激系统内的神经适应机制，重点关注扩展杏仁核神经回路内新发现的脑唤醒应激系统：加压素，下丘脑泌素（食欲素）和伤害感受素。在本研究中，接受检验的总体假设是，杏仁核和/或基底外侧杏仁核的中央核、终纹床核和杏仁核中的加压素和下丘脑泌素活性增加以及伤害感受素活性降低是与依赖性相关的饮酒增强的原因，并且这些系统通过激活扩展杏仁核中的CRF相互作用。具体目标是：目的：探讨选择性拮抗剂/激动剂作用下，大鼠杏仁核内加压素（SpA 1）、食欲素（SpA 2）和痛敏素（SpA 3）在酒精戒断过程中增加乙醇自我给药的作用，以及促肾上腺皮质激素释放因子（CRF）在大鼠酒精依赖过程中加压素、食欲素和痛敏素（SpA 4）作用中的作用。为了实现这些目标，将采用一系列在大鼠中给予选择性受体亚型拮抗剂和/或激动剂的研究，以及在依赖性大鼠中使用过量乙醇自我给药的可靠动物范例测量神经元活化（cFos）的神经解剖学研究。结果将提供新颖的和创新的见解的神经基板的情绪失调的关键大脑动机领域，形成过度饮酒与依赖的基础，因此，将提供新的目标，诊断的脆弱性，预防和治疗酒精依赖。考虑到直接病理学、间接医疗和社会后果以及生产力损失，酗酒每年给美国社会造成超过2000亿美元的巨大损失。酒精中毒是一种慢性复发性疾病，其特征是寻求和服用酒精的强迫性，并与大脑唤醒和情感系统的失调有关，这些系统与酒精依赖的发展密切相关。本提案中概述的研究将确定与这些产生酒精依赖的大脑情感系统的扰动有关的新的神经化学机制。结果将提供新颖和创新的见解的神经基板的情绪失调的关键大脑动机领域，形成过度饮酒与依赖的基础，因此，将提供新的目标，诊断的脆弱性，预防和治疗酒精依赖。

DESCRIPTION (provided by applicant): Alcoholism is a chronically relapsing disorder characterized by a compulsion to seek and take alcohol and has been linked to dysregulation of the brain arousal and emotional systems critically involved in both the positive and negative reinforcement important for the development of alcoholism. Dependence and the vulnerability to relapse has been argued to include counteradaptive neurochemical events within the brain emotional systems normally used to maintain emotional homeostasis (Koob and Le Moal, 2005, 2008, Appendix) and produce compulsive drinking via negative reinforcement mechanisms. In the previous funding period, we characterized key roles of increased activity of the brain stress systems corticotropin-releasing factor (CRF) and norepinephrine and decreased activity in the neuropeptide Y anti-stress system in dependence-induced drinking. The research plan of the present competitive renewal will be to continue the studies on the mechanisms of neuroadaptation within brain arousal-stress systems during the development of excessive drinking induced by dependence with a focus on newly identified brain arousal-stress systems within the neurocircuitry of the extended amygdala: vasopressin, hypocretin (orexin) and nociceptin. The overall hypothesis under test in the present proposal is that increased vasopressin and hypocretin activity and decreased nociceptin activity in the central nucleus of the amygdala and/or basolateral amygdala, bed nucleus of the stria terminalis, and nucleus accumbens are responsible for the enhanced drinking associated with a dependence, and that these systems interact via an activation of CRF in the extended amydala. The Specific Aims are: To explore the role of vasopressin (SpA 1), orexin (SpA 2), and nociceptin (SpA 3) in the extended amygdala on increased ethanol self-administration during withdrawal in rats using administration of selective antagonists/agonists, and to explore the role of corticotropin releasing factor (CRF) in the actions of vasopressin, orexin and nociceptin in rats during dependence (SpA 4). To accomplish these aims, a series of studies with administration of selective receptor subtype antagonists and/or agonists in rats and neuroanatomical studies with measures of neuronal activation (cFos) using a reliable animal paradigm of excessive ethanol self-administration in dependent rats will be employed. Results will provide novel and innovative insights into the neural substrates of emotional dysregulation in key brain motivational areas that form the basis of excessive drinking associated with dependence, and as such, will provide new targets for diagnosi of vulnerability, prevention and treatment of alcohol dependence. PUBLIC HEALTH RELEVANCE Alcoholism produces an enormous cost to United States society of over 200 billion dollars per year when considering direct pathology, indirect medical and social consequences and loss of productivity. Alcoholism is a chronically relapsing disorder characterized by a compulsion to seek and take alcohol and has been linked to dysregulation of the brain arousal and emotional systems critically involved in the development of dependence on alcohol. The studies outlined in the present proposal will identify novel neurochemical mechanisms involved in the perturbations of these brain emotional systems that produce dependence on alcohol. Results will provide novel and innovative insights into the neural substrates of emotional dysregulation in key brain motivational areas that form the basis of excessive drinking associated with dependence, and as such, will provide new targets for diagnosis of vulnerability, prevention and treatment of alcohol dependence.