Preclinical Assessment of Medications for Alcohol Abuse

酒精是美国最常见的滥用药物之一，10%的人口受到酒精的影响 在他们生命中的某个时刻会产生依赖。一个重要的新焦点是开发新的药物来 帮助酒精依赖患者减少饮酒，促进戒酒。新的潜在目标 药物是大脑奖励系统的多种神经递质系统，包括伽马- 氨基丁酸(GABA)、谷氨酸、多巴胺、大麻和阿片肽，它们似乎是 与酒精的强化作用有关。强迫性饮酒可以概念化为一系列 以饮酒告终的复杂行为。这种复杂的行为序列可以是 以实验室动物为模型，使用链式加固计划。拟议的研究将利用 在初始中性提示(灯光和音调)的3个不同部分期间呈现的过程 钢筋的链式明细表。每个组件都与可操作的响应需求相关联 这与一个明显的线索相关。满足第二个组件中的响应要求是 进行到第三个也是最后一个组件所必需的。主要增强剂(酒精或首选的非 酒精饮料；唐)将仅在最终组件中用于自我管理。这 程序允许测量与饮酒预期、寻求、消费相关的行为 并在同一个实验过程中进行加固。目前的提案将评估……的效果 新建议的酒精类药物(如托吡酯、巴氯芬、3-PBC和SR141716)用于减少酒精含量 寻求和消费。此外，目前FDA批准的药物(纳曲酮和氨基己酸酯)将 也要进行评估以进行比较。将检验以下假设：1)测试药物将减少 酒精自我给药行为和饮酒量，2)测试药物会降低 获得酒精的动机，通过推迟开始饮酒和减少 受试者为获得酒精而从事的最大工作量，3)自我减少 测试药物产生的用药和消耗量将大于唐药，以及4) 与唐相比，测试药物会更大地降低人们获得酒精的动机。这些研究将 提供关于化合物不同行为功效的重要信息，这些信息以前是无法获得的 这种靶向受体机制被认为在维持饮酒和酒精方面有影响- 寻找与人类强制饮酒和复发相关的行为。

Alcohol is one of the most commonly abused drugs in the US, with 10% of the population affected by alcohol dependence at some point in their lives. An important newfocus is the development of new medications to help alcohol dependent patients reduce their alcohol use and promote abstinence. Potential targets for new medications are the multiple neurotransmitter systems of the brain reward systems including gamma- aminobutyric acid (GABA), glutamate, dopamine, cannabinoid and opioid peptides, which appear to be involved in the reinforcing effects of alcohol. Compulsive drinking can be conceptualized as a sequence of complex behaviors that terminate in alcohol consumption. Such complex sequences of behavior can be modeled in laboratory animals using chained schedules of reinforcement. The proposed studies will utilize a procedure in which initially neutral cues (lights and tones) are presented during 3 distinct components of a chained schedule of reinforcement. Each component is associated with an operant response requirement that is correlated with a distinct cue. Fulfilling the response requirement in the second component is necessary to progress to the third and final component. The primary reinforcer (alcohol or a preferred non- alcoholic beverage; Tang) will be available for self-administration only in the final component. This procedure allows the measurement of behaviors associated with alcohol anticipation, seeking, consumption and reinforcement within the same experimental session. The current proposal will evaluate the efficacyof newly proposed alcohol medications (e.g., topiramate, baclofen, 3-PBC and SR141716) in reducing alcohol seeking and consumption. In addition, current FDA-approved medications (naltrexone and acamprosate) will also be evaluated for comparison. The following hypotheses will be tested: 1) Test drugs will decrease alcohol self-administration behaviors and the amount of alcohol consumed, 2) Test drugs will decrease the motivation to gain access to alcohol, as measured by delaying onset of drinking and by reducing the maximum amount of work the subject will engage in to gain access to alcohol, 3) Decreases in self- administration and consumption produced by the test drugs will be greater for alcohol than for Tang, and 4) Test drugs will decrease the motivation to gain access to alcohol more than for Tang. These studies will provide important, previously unavailable, information on the differential behavioral efficacy of compounds that target receptor mechanisms believed to be influential in maintaining alcohol drinking and alcohol- seeking behaviors that are relevant to compulsive alcohol use and relapse in humans.