Preclinical Assessment of Medications for Alcohol Abuse

酒精滥用药物的临床前评估

• 批准号: 10380634
• 负责人: Elise M Weerts
• 金额: $ 68.04万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380634
• 关键词: Abstinence; Agonist; Alcohol abuse; Alcohol consumption; Alcohols; Animal Model; Baclofen; Behavior; Behavioral; Beverages; Blood alcohol level measurement; Cannabidiol; Cannabinoids; Characteristics; Chronic; Clinic; Consumption; Control Groups; Cues; Data; Development; Disulfiram; Dose; Drug Controls; Drug Side Effects; Drug usage; Eating; Evaluation; Extinction (Psychology); FDA approved; Goals; Health; Human; Incidence; Injections; Intake; Laboratory Animal Models; Ligands; Link; Matched Group; Measurement; Modeling; Naltrexone; Neuropeptides; Nicotine; Nicotine Dependence; Nicotinic Receptors; Nociception; Opioid Peptide; Opioid Receptor; Oral; Outcome; Oxytocin; Patients; Pattern; Peptide Receptor; Pharmaceutical Preparations; Pharmacology; Phase; Pre-Clinical Model; Procedures; Recording of previous events; Reinforcement Schedule; Relapse; Resistance; Risk; Self Administration; Signal Transduction; Smoker; Stimulus; Testing; Therapeutic; Therapeutic Index; Time; Tobacco use; Water consumption; acamprosate; alcohol abuse therapy; alcohol effect; alcohol misuse; alcohol reinforcement; alcohol related problem; alcohol risk; alcohol seeking behavior; alcohol use disorder; antagonist; behavior observation; binge drinking; biobehavior; cost; data integration; drinking; drug candidate; drug misuse; drug testing; improved; motor deficit; nicotine use; nicotine user; non-alcoholic; non-smoker; nonhuman primate; novel; novel therapeutics; pre-clinical assessment; programs; reduced alcohol use; reinforcer; response; side effect; therapy development; treatment optimization; treatment strategy; varenicline

Alcohol is one of the most widely used and misused drugs in the US. There is a critical need to continue to improve AUD treatment and develop new medications to reduce alcohol use and to include nicotine co-use in evaluations of candidate medications. This project proposes to investigate biobehavioral mechanisms underlying alcohol and nicotine use and co-use, and to test candidate medications in two animal models developed specifically for testing medications for alcohol abuse, and alcohol and nicotine co-use. The first model uses a Chained Schedule of Reinforcement (CSR) procedure in which seeking and consumption occur in the context of distinct environmental cues and behavioral contingencies to the influence of environmental stimuli on the drive to drink and the persistence of behaviors associated with chronic drinking. Two 2 matched groups of NHP with extensive histories of self-administration of alcohol (Alcohol group) or the non-alcoholic beverage (Control group) will be utilized. The second model is a new Alcohol and Nicotine Concurrent Access (ANCA) procedure in which oral alcohol and IV nicotine were concurrently available for self-administration. A functional assessment battery provides assessment of drug side effects. Aim 1 will determine whether test drugs reduce alcohol seeking and self-administration in the CSR under conditions of ongoing drinking and abstinence. Aim 2 will determine whether test drugs reduce alcohol and nicotine self-administration independently or concurrently under single drug access or ANCA procedures. Aim 3 will determine incidence of side effects of test drugs in the functional assessment battery. Drug candidates include bifunctional and universal opioid receptor (OR) ligands with different pharmacological profiles at OR subtypes, a universal OR/nociception opioid peptide (NOP) receptor ligand, the cannabinoid constituent cannabidiol (CBD), the neuropeptide oxytocin, and a nicotinic acetylcholine receptor partial agonist/antagonist varenicline. Naltrexone will be tested as a positive control and comparator. A drug with therapeutic potential would be one that reduces cue-maintained seeking, and decreases alcohol self-administration, and has a low side-effect profile. A drug with therapeutic potential in alcohol and nicotine co-users would decrease alcohol self-administration without increasing nicotine self-administration, and ideally would reduce self-administration of both drugs. Integration these data will provide new information on the behavioral and neuropharmacological mechanisms involved in alcohol abuse and alcohol/nicotine co-use. Comparison of dose effect functions and efficacy across models can inform treatment strategies for optimal dosing and timing of treatment. This information will ultimately facilitate medication development for the treatment of alcohol misuse and AUD.

酒精是美国使用最广泛和滥用的药物之一。迫切需要继续 改善AUD治疗并开发新的药物以减少酒精的使用，并包括尼古丁共同使用 评估候选药物。该项目建议研究生物行为机制 基础酒精和尼古丁的使用和共用，并在两种动物模型中测试候选药物 专门针对测试酗酒的药物，酒精和尼古丁共同使用。第一个 模型使用锁定的加固时间表（CSR）程序，在此过程中发生 在环境影响的不同环境线索和行为偶然性的背景下 刺激饮酒的动力以及与慢性饮酒有关的行为的持久性。两个2匹配 NHP组具有广泛的酒精（酒精组）或非酒精性的自我管理史 将使用饮料（对照组）。第二个模型是新的酒精和尼古丁并发 （ANCA）同时可以自我管理的口服酒精和静脉尼古丁的程序。一个 功能评估电池可评估药物副作用。 AIM 1将确定是否测试 在持续饮酒和 节制。 AIM 2将确定测试药物是否减少酒精和尼古丁自我给药 独立或同时在单一药物访问或ANCA程序下。 AIM 3将确定发生率 在功能评估电池中测试药物的副作用。候选药物包括双功能和 通用阿片受体（OR）配体具有不同的药理学特征或亚型的药理学特征，一种通用 或/伤害感受阿片类肽（NOP）受体配体，大麻素组成大麻二酚（CBD）， 神经肽催产素和烟碱乙酰胆碱受体部分激动剂/拮抗剂varenicline。纳曲酮 将作为阳性对照和比较器进行测试。具有治疗潜力的药物将是减少的药物 提示维护的寻求，并减少酒精自给自足，并且副作用较低。药物 在酒精和尼古丁共同使用者中的治疗潜力将减少酒精的自我管理而不会 增加尼古丁的自我给药，理想情况下会减少两种药物的自我给药。一体化 这些数据将提供有关涉及的行为和神经药理机制的新信息 酒精滥用和酒精/尼古丁共同使用。比较模型的剂量效应功能和功效 可以为治疗策略提供最佳剂量和治疗时间的信息。这些信息最终将 促进治疗滥用酒精和AUD的药物开发。