Neuropharmacology of Ethanol Reinforcement

描述（由申请人提供）：酒精中毒是一种慢性复发的疾病，其特征是强迫寻求和服用酒精，并且与大脑觉醒和情绪系统的失调有关，这些系统与酒精中毒的发展至关重要的正强化和负强化都有关系。依赖性和易复发性被认为包括通常用于维持情绪稳态的大脑情绪系统中的反适应神经化学事件（Koob和Le Moal， 2005,2008，附录），并通过负强化机制产生强迫性饮酒。在之前的资助期内，我们描述了脑应激系统促肾上腺皮质激素释放因子（CRF）和去甲肾上腺素活性增加以及神经肽Y抗应激系统活性降低在依赖诱导饮酒中的关键作用。本课题的研究计划是继续研究过度饮酒依赖发展过程中脑唤醒应激系统的神经适应机制，重点研究扩展杏仁核神经回路中新发现的脑唤醒应激系统：抗利尿激素、下丘脑分泌素（食欲素）和痛觉肽。本研究的总体假设是，杏仁核中央核和/或基底外侧杏仁核、终纹床核和伏隔核中抗利尿激素和下丘脑分泌素活性的增加和痛觉肽活性的降低是与依赖相关的饮酒增强的原因，这些系统通过扩展杏仁核中CRF的激活相互作用。具体目的是：探讨后叶加压素（SpA 1）、食欲素（SpA 2）和痛觉肽（SpA 3）在使用选择性拮抗剂/激动剂的大鼠戒断期间对乙醇自我给药增加的作用，以及探讨促肾上腺皮质激素释放因子（CRF）在依赖期大鼠抗利尿素、食欲素和痛觉肽的作用（SpA 4）。为了实现这些目标，将在大鼠中使用选择性受体亚型拮抗剂和/或激动剂进行一系列研究，并在依赖大鼠中使用可靠的过度乙醇自我给药动物范式进行神经活化（cFos）测量的神经解剖学研究。研究结果将提供新的和创新的见解，以了解在形成过度饮酒相关依赖基础的关键大脑动机区域中情绪失调的神经基质，因此，将为诊断脆弱性、预防和治疗酒精依赖提供新的目标。考虑到直接病理、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的巨大损失超过2000亿美元。酒精中毒是一种慢性复发的疾病，其特征是强迫寻求和服用酒精，并与大脑觉醒和情绪系统的失调有关，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涉及这些产生酒精依赖的大脑情绪系统扰动的新的神经化学机制。研究结果将提供新的和创新的见解，以了解在形成过度饮酒相关依赖基础的关键大脑动机区域中情绪失调的神经基质，因此，将为诊断脆弱性、预防和治疗酒精依赖提供新的目标。

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.