Neuropharmacology of Ethanol Reinforcement

乙醇强化的神经药理学

• 批准号: 8066453
• 负责人: George F. Koob
• 金额: $ 42.92万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066453
• 关键词: Abstinence; Acute; Agonist; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amygdaloid structure; Animal Model; Animals; Anxiety; Area; Arousal; Automobile Driving; Aversive Stimulus; Behavior; Blood alcohol level measurement; Brain; Cell Nucleus; Chronic; Corticotropin-Releasing Hormone; Data; Dependence; Development; Diagnosis; Disease; Elements; Emotional; Ethanol; Event; Excision; Exhibits; Exposure to; Floor; Funding; Health; Heavy Drinking; Homeostasis; Impulsivity; Individual; Intake; Laboratories; Link; Measures; Medial; Medical; Modeling; Morphology; Negative Reinforcements; Neurobiology; Neurons; Neuropharmacology; Neurotransmitters; Norepinephrine; Nucleus Accumbens; Pathology; Pharmaceutical Preparations; Positive Reinforcements; Prevention; Probability; Process; Progress Reports; Psychological reinforcement; Rattus; Relapse; Research; Role; Saccharin; Schedule; Self Administration; Series; Societies; Solutions; Source; Stimulus; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Substance Addiction; Sweetening Agents; System; Testing; Time; United States; Vasopressin Antagonist; Vasopressins; Walkers; Wistar Rats; Withdrawal; alcohol reinforcement; alcohol reward; basal forebrain; base; cost; drinking; dysphoria; hedonic; hypocretin; innovation; insight; negative emotional state; neuroadaptation; neurochemistry; neuropeptide Y; nociceptin; novel; prevent; productivity loss; receptor; relating to nervous system; response; social; social movement; vapor

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.

描述（由申请人提供）：酒精中毒是一种长期复发的疾病，其特征是强迫寻求和服用酒精，并且与大脑唤醒和情感系统的失调有关，这与对酒精中毒发展重要的积极和负面增强非常重要。依赖性和复发的脆弱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自适应神经化学事件（Koob and Le Moal，2005，2008，附录，附录），并通过负强化机制产生强迫性饮酒。在上一个资金期间，我们表征了脑应力系统增加的活动性角色的关键作用，皮质激素释放因子（CRF）和去甲肾上腺素以及神经肽y抗压力系统在依赖性诱导的饮酒中的活性降低。目前的竞争性更新的研究计划将是继续研究大脑唤醒压力系统内神经适应机制的研究，这是在依赖性诱导的过量饮酒期间，重点是对新近识别的脑唤醒压力系统的神经循环系统的神经循环系统，而杏仁核的神经循环系统是：加索蛋白，降压素，甲固醇（orexcitin）和nicectin和nocctin and nocctin and nocctin and nocctin）。 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.具体目的是：探索加压素（SPA 1），Orexin（Spa 2）和NociTptin（Spa 3）在延长的杏仁核中使用选择性拮抗剂/激动剂的给药，并探索CROSITICOPINSINERICERINSINERICTICROPINSINERINGINERECOPIN（CRFFOSIN）的作用（Crff ins in Crff ins in Crff ins in nive）在大鼠戒断期间增加乙醇的作用（Crff ins）。在依赖性期间，大鼠中的nocceptin（Spa 4）。为了实现这些目的，一系列研究对大鼠的选择性受体亚型拮抗剂和/或激动剂的给药，以及神经元激活（CFO）的神经解剖学研究（CFO），使用过度乙醇自我服用的可靠动物范式用于依赖大鼠中。结果将为关键的大脑动机区域中的神经失调的神经底物提供新颖的见解，这是与依赖相关的过度饮酒的基础，因此，将为易受酒精依赖的脆弱性，预防和治疗的诊断提供新的目标。当考虑直接病理学，间接医疗和社会后果以及生产力丧失时，公共卫生相关性酒精中毒每年为美国社会产生巨大的成本。酒精中毒是一种长期复发性疾病，其特征是强迫寻求和服用酒精，并且与大脑唤醒和情感系统的失调有关，与依赖酒精的依赖发展有关。本提案中概述的研究将确定与这些大脑情绪系统扰动有关的新型神经化学机制，这些系统产生了对酒精的依赖。结果将为关键的大脑动机区域的神经失调的神经底物提供新颖的见解，这是与依赖相关的过度饮酒的基础，因此，将为诊断脆弱性，预防和治疗酒精依赖性提供新的目标。