Preclinical Assessment of Medications for Alcohol Abuse

酒精滥用药物的临床前评估

• 批准号: 8639331
• 负责人: Elise M Weerts
• 金额: $ 50.68万
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639331
• 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; 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.

描述（由申请人提供）：酒精是美国最常滥用的药物之一，10% 的人口在一生中的某个阶段受到酒精依赖的影响。迫切需要开发新药物来帮助酒精依赖患者减少饮酒并促进戒酒。复发的关键预测因素之一是对酒精的渴望和冲动的严重程度，这被认为是由于经典条件状态以及与长期饮酒和戒酒相关的神经适应性变化所致。新药物的潜在目标包括γ-氨基丁酸（GABA）、谷氨酸和阿片类药物系统，这些系统会因长期过量饮酒而失调。在当前的提案中，我们将评估 kappa-阿片受体拮抗剂、苯二氮卓-GABAA α1 受体拮抗剂/部分激动剂和代谢型谷氨酸受体调节剂，作为减少持续饮酒和强迫性饮酒的潜在 AUD 药物。拟议的研究将利用经过验证的狒狒饮酒程序，该程序结合了经典条件反射和操作性条件反射，并模拟了人类饮酒问题的特征模式（“太多、太快、太频繁”）。该过程由一系列单独的行为意外事件组成，每个行为意外事件都与一个独特的线索相关，以形成反应链的不同环节，最终导致酒精强化。该程序可以检查持续饮酒期间寻求酒精和自我管理反应之间的关系，以及研究禁欲期间持续线索维持行为的能力。我们建议检查测试药物在戒酒和饮酒条件下对酒精维持行为的影响，以及 AUD 治疗常见的不同给药方案。目标 1 将确定测试药物是否选择性地减少对酒精的渴求并改变日常饮酒过程中的自我管理模式。目标 2 将确定测试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。目标 3 将确定在戒酒期间使用测试药物开始和维持亚慢性治疗是否会选择性地减少恢复饮酒后的寻求和摄入。目标 4 将确定在持续饮酒和戒酒的情况下服用测试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会减少戒酒期间线索维持的酒精寻求，减少持续饮酒期间的寻求和自我给药，并且产生很少的副作用。酒精组和对照组的剂量效应函数的比较将提供每种测试药物在饮酒和戒酒条件下的治疗指数。这些研究将为针对人类强迫性饮酒和复发相关受体机制的化合物的不同行为功效提供重要的新信息。