Preclinical Assessment of Medications for Alcohol Abuse

酒精滥用药物的临床前评估

• 批准号: 8127653
• 负责人: Elise M Weerts
• 金额: $ 31.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127653
• 关键词: Abstinence; Address; Affect; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholic Beverages; Alcohols; Animals; Antiepileptic Agents; Attenuated; Baclofen; Behavior; Behavioral; Benzodiazepines; Brain; CNR1 gene; Cannabinoids; Clinical Trials; Complex; Consumption; Cues; Data; Development; Disulfiram; Dopamine; Dose; Drug Kinetics; Drug Metabolic Detoxication; Flavoring; Food; Glutamates; Goals; Heavy Drinking; Human; In complete remission; Influentials; Laboratory Animals; Laboratory Study; Link; Liquid substance; Literature; Measures; Modeling; Motivation; Naltrexone; Neurotransmitters; Opioid Peptide; Oranges; Outcome; Papio; Patients; Pharmaceutical Preparations; Population; Pre-Clinical Model; Primates; Procedures; Psychological reinforcement; Reinforcement Schedule; Relapse; Relative (related person); Research Personnel; Rewards; SR141716; Schedule; Self Administration; Self-Administered; Specificity; Stimulus; System; Testing; Treatment Efficacy; United States Food and Drug Administration; Work; acamprosate; alcohol abstinence; alcohol availability; alcohol craving; alcohol effect; alcohol reinforcement; alcohol relapse; alcohol seeking behavior; alcoholism therapy; behavior measurement; craving; drinking; drinking onset; drug of abuse; drug reinforcement; drug testing; gamma-Aminobutyric Acid; improved; meetings; non-alcoholic; nonhuman primate; novel; pre-clinical; programs; receptor; reduced alcohol use; reinforcer; response; sex; topiramate

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.

酒精是美国最常见的滥用药物之一，10%的人口受酒精影响 在生活中的某个时刻，一个重要的新焦点是开发新的药物， 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，大麻素和阿片肽，这似乎是 参与酒精的强化作用。强迫性饮酒可以被概念化为一系列 复杂的行为，终止于酒精消费。这种复杂的行为序列可以是 在实验室动物中使用强化的链式时间表建模。拟议的研究将利用一个 一个程序，在一个程序的3个不同的组成部分，最初的中性线索（灯光和音调）， 强化的连锁计划每个组成部分都与一个操作性响应要求相关联 这与一个独特的线索有关。满足第二部分中的响应要求是 这是进入第三个也是最后一个阶段所必需的。主要的酒精（酒精或优选的非酒精） 酒精饮料; Tang）仅在最终组分中可用于自我给药。这 该程序可以测量与酒精预期、寻求、消费相关的行为 在同一个实验阶段中进行强化。目前的提案将评估以下方面的效力： 新提出的酒精药物（例如，托吡酯、巴氯芬、3-PBC和SR 141716）降低酒精含量 追求与消费。此外，目前FDA批准的药物（纳洛酮和阿坎酸）将 也可以进行比较。将检验以下假设：1）试验药物将减少 酒精自我管理行为和饮酒量，2）试验药物将减少 获得酒精的动机，通过延迟饮酒开始和减少 受试者将从事的最大工作量，以获得酒精，3）自我减少， 试验药物的给药和消耗量对于酒精的影响大于Tang，以及4） 测试药物将减少获得酒精的动机比唐。这些研究将 提供了重要的，以前无法获得的，关于化合物的不同行为功效的信息 这种靶向受体机制被认为对维持饮酒和酒精有影响， 寻找与人类强迫性饮酒和复发有关的行为。