Preclinical Assessment of Medications for Alcohol Abuse

酒精滥用药物的临床前评估

• 批准号: 8828526
• 负责人: Elise M Weerts
• 金额: $ 43.56万
• 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/8828526
• 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; 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）：酒精是美国最常见的药物之一，其中10％的人口在其生活中的某个时候受酒精依赖的影响。迫切需要开发新药物来帮助依赖酒精的患者减少饮酒并促进戒酒。复发的主要预测因素之一是渴望酒精和饮酒的渴望的严重性，这被认为是由于经典的状态以及与长期饮酒和戒酒有关的神经适应性变化。新药物的潜在靶标包括γ-氨基丁酸（GABA），谷氨酸和阿片类药物系统，它们因长期过度饮酒而失调。在目前的提案中，我们将评估Kappa-阿片受体拮抗剂，苯二氮卓类-Gabaa Alpha1受体拮抗剂/部分激动剂和代谢性谷氨酸受体的调节剂，作为潜在的AUD药物，以减少暂时的酒精寻求和强迫性饮酒。拟议的研究将在狒狒中利用经过验证的饮酒程序，结合了经典和操作条件，并模拟人类问题饮酒的特征模式（“太多，太快，太快，太频繁”）。该过程由一系列单独的行为偶然性组成，每个偶然性都与独特的提示相关，以形成一系列反应链的不同链接，这些响应最终会重复进行酒精加强。该程序允许研究持续饮酒期间寻求酒精和自我管理反应之间的关系，以及在戒酒期间研究持久性提示维护行为的能力。我们建议在禁欲和酒精可用性的条件下检查对药物对维护饮酒的行为的影响，以及AUD治疗常见的不同剂量方案。 AIM 1将确定测试药物在每天获得酒精期间是否有选择地减少寻求酒精并改变自我管理模式。 AIM 2将确定测试药物是否有助于在持续酒精获取和戒酒期间灭绝酒精定向的反应。 AIM 3将确定在禁欲期间使用测试药物进行亚少生治疗的启动和维持是否会选择性地减少返回酒精饮酒后寻求和摄入。 AIM 4将确定在持续的饮酒和戒酒条件下施用的测试药物的副作用的发生率。来自这些目标的数据的整合将用于确定每种药物的治疗潜力。也就是说，一种具有治疗潜力的药物会减少提示在戒酒期间寻求提示的酒精，减少持续酒精期间的寻求和自我管理，而产生的副作用很少。在酒精和对照组中的剂量效应功能的比较将在酒精获取和戒酒的条件下提供每种测试药物的治疗指数。这些研究将提供有关化合物的差异行为疗效的重要新信息，这些化合物的差异性行为疗效靶向与强迫性饮酒和人类复发相关的受体机制。