Preclinical Assessment of Medications for Alcohol Abuse

酒精是美国最常见的滥用药物之一，10%的人口在生活中的某个时候受到酒精依赖的影响。一个重要的新焦点是开发新的药物，以帮助酒精依赖患者减少饮酒和促进戒酒。新药物的潜在目标是大脑奖励系统的多种神经递质系统，包括γ-氨基丁酸（GABA）、谷氨酸、多巴胺、大麻素和阿片肽，它们似乎参与了酒精的强化作用。强迫性饮酒可以被概念化为一系列复杂的行为，最终以饮酒结束。这种复杂的行为序列可以在实验室动物中使用链式强化时间表进行建模。拟议的研究将利用一个程序，其中最初的中性线索（灯光和音调），在3个不同的组成部分的链式强化。每个组成部分都与一个操作性反应要求相关联，该要求与一个不同的线索相关联。满足第二部分的响应要求是进入第三部分和最后一部分的必要条件。主要饮料（酒精或首选的非酒精饮料; Tang）仅在最终组分中可用于自我给药。这个过程允许测量行为与酒精的预期，寻求，消费和强化在同一个实验会话。目前的提案将评估新提出的酒精药物的疗效（例如，托吡酯、巴氯芬、3-PBC和SR 141716）在减少酒精寻求和消费方面的作用。此外，目前FDA批准的药物（纳洛酮和阿坎酸）也将进行评估以进行比较。将检验以下假设：1）试验药物将减少酒精自我给药行为和酒精消耗量，2）试验药物将减少获得酒精的动机，如通过延迟饮酒开始和减少受试者将参与获得酒精的最大工作量所测量的，3）酒精对受试药物产生的自我给药和消耗的减少大于Tang，以及4）受试药物对获得酒精的动机的减少大于Tang。这些研究将提供关于化合物的不同行为功效的重要的、先前不可用的信息，所述化合物靶向被认为在维持与人类强迫性酒精使用和复发相关的饮酒和寻求酒精的行为中有影响的受体机制。

DESCRIPTION (provided by applicant): 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 new focus 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 efficacy of 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.