Preclinical Assessment of Medications for Alcohol Abuse

酒精滥用药物的临床前评估

• 批准号: 9355937
• 负责人: Elise M Weerts
• 金额: $ 9.98万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9355937
• 关键词: Abstinence; Adverse effects; Affect; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Anatomy; Animals; Behavior; Behavioral; Benzodiazepines; Beverages; Blood alcohol level measurement; Characteristics; Chronic; Control Groups; Cues; Data; Development; Dose; Evaluation; Extinction (Psychology); FDA approved; Glutamate Receptor; Glutamates; Goals; Health; Heavy Drinking; Human; Incidence; Intake; Knowledge; Laboratory Animals; Learning; Link; Maintenance; Metabotropic Glutamate Receptors; Modeling; Motivation; Naltrexone; National Institute on Alcohol Abuse and Alcoholism; Neurotransmitters; Operant Conditioning; Opioid; Opioid Receptor; Papio; Patients; Pattern; Pharmaceutical Preparations; Phylogeny; Physiology; Population; Procedures; Process; Regimen; Reinforcement Schedule; Relapse; Resistance; Risk; Rodent; Rodent Model; Self Administration; Self-Administered; Severities; Specificity; System; Testing; Therapeutic; Therapeutic Index; Translational Research; acamprosate; alcohol abstinence; alcohol availability; alcohol craving; alcohol cue; alcohol reinforcement; alcohol relapse; alcohol seeking behavior; alcoholism therapy; chronic alcohol ingestion; classical conditioning; craving; data integration; deprivation; drinking; drug efficacy; drug of abuse; drug testing; expectation; gamma-Aminobutyric Acid; high risk drinking; improved; neurochemistry; non-alcoholic; pre-clinical; problem drinker; receptor; relapse patients; response; treatment effect; treatment strategy

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. There is a critical need for the development of new medications to help alcohol dependent patients reduce their alcohol use and promote abstinence. One of key predictors of relapse is severity of alcohol craving and urge to drink, which are thought to be due to classically conditioned states, and neuroadaptive changes associated with chronic alcohol consumption and abstinence. Potential targets for new medications include gamma-aminobutyric acid (GABA), glutamate, and opioid systems, which become dysregulated with chronic excessive alcohol consumption. In the current proposal, we will evaluate a kappa-opioid receptor antagonist, benzodiazepine-GABAA alpha1 receptor antagonists/partial agonists and modulators of metabotropic glutamate receptors, as potential AUD medications to reduce persistent alcohol seeking and compulsive drinking. The proposed studies will utilize a validated drinking procedure in baboons that combines classical and operant conditioning and models characteristic patterns of human problem drinking ('too much, too fast, too often'). The procedure consists of a sequence of separate behavioral contingencies, each of which is correlated with a unique cue, to form different links of a chain of responses that ultimately resul in alcohol reinforcement. This procedure allows examination of the relationships between alcohol seeking and self-administration responses during ongoing alcohol consumption, as well as the ability to study persistence cue-maintained behaviors during abstinence. We propose to examine test drug effects on alcohol-maintained behaviors under conditions of abstinence and alcohol availability, and different dosing regimens common to AUD treatment. Aim 1 will determine whether test drugs selectively reduce alcohol seeking and alter patterns of self-administration during daily access to alcohol. Aim 2 will determine whether test drugs facilitate extinction of alcohol-directed responding during ongoing alcohol access and during abstinence. Aim 3 will determine whether initiation and maintenance of subchronic treatment with test drugs during abstinence selectively reduces seeking and intake upon return to alcohol access. Aim 4 will determine incidence of side effects of test drugs administered under conditions of ongoing drinking and abstinence. Integration of the data from these aims will be used to determine the therapeutic potential of each drug. That is, a drug with therapeutic potential would reduce cue-maintained alcohol seeking during abstinence, reduce seeking and self-administration during ongoing alcohol access, and produce few side effects. Comparison of dose effect functions in the alcohol and control groups will provide a therapeutic index of each test drug under conditions of alcohol access and abstinence. These studies will provide important, new information on the differential behavioral efficacy of compounds that target receptor mechanisms 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%的人口在生活中的某个时候受到酒精依赖的影响。迫切需要开发新的药物来帮助酒精依赖患者减少酒精使用并促进戒酒。复发的关键预测因素之一是酒精渴望和饮酒冲动的严重程度，这被认为是由于经典的条件状态，以及与长期饮酒和戒酒相关的神经适应性变化。新药物的潜在靶点包括γ-氨基丁酸（GABA）、谷氨酸和阿片系统，这些系统会随着慢性过量饮酒而失调。在当前的提案中，我们将评估一种κ阿片受体拮抗剂、苯二氮卓类-GABAA α 1受体拮抗剂/部分激动剂和代谢型谷氨酸受体调节剂，作为减少持续性酒精寻求和强迫性饮酒的潜在AUD药物。拟议的研究将利用狒狒的有效饮酒程序，该程序结合了经典和操作性条件反射，并模拟了人类问题饮酒的特征模式（“太多，太快，太频繁”）。这个过程由一系列独立的行为偶然事件组成，每一个事件都与一个独特的线索相关，形成一系列反应的不同环节，最终导致酒精强化。这个程序允许检查酒精寻求和自我管理的反应之间的关系，在持续的酒精消费，以及研究持久性线索保持行为在禁欲的能力。我们建议在戒酒和酒精可用性以及AUD治疗常见的不同给药方案的条件下检查试验药物对酒精维持行为的影响。目标1将确定测试药物是否选择性地减少酒精寻求和改变模式的自我管理在日常访问酒精。目标2将确定试验药物是否有助于在持续饮酒和戒酒期间消除酒精导向反应。目的3将确定在戒酒期间开始和维持试验药物亚慢性治疗是否选择性地减少恢复酒精接触后的寻求和摄入。目的4将确定在持续饮酒和戒酒条件下给予试验药物的副作用发生率。这些目标的数据整合将用于确定每种药物的治疗潜力。也就是说，具有治疗潜力的药物将减少戒酒期间的线索维持酒精寻求，减少持续酒精获取期间的寻求和自我管理，并且产生很少的副作用。酒精组和对照组的剂量效应函数比较将提供酒精接触和戒酒条件下每种试验药物的治疗指数。这些研究将提供重要的，新的信息的差异行为疗效的化合物，目标受体机制相关的强迫性酒精使用和复发的人。