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Preclinical Assessment of Medications for Alcohol Abuse

酒精滥用药物的临床前评估

基本信息

批准号：
10599097
负责人：
Elise M Weerts
金额：
$ 67.4万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-28 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599097
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 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 Phase Pre-Clinical Model Procedures Recording of previous events Reinforcement Schedule Relapse Resistance Risk Self Administration Signal Transduction Smoker Stimulus Testing Therapeutic Therapeutic Index 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 self-administration nicotine use nicotine user non-alcoholic non-smoker nonhuman primate novel novel therapeutics pharmacologic pre-clinical assessment programs reduced alcohol use reinforcer response side effect therapy development treatment optimization treatment strategy varenicline

项目摘要

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.

酒精是美国最广泛使用和滥用的药物之一。迫切需要继续改善AUD治疗，开发新的药物以减少酒精使用，并将尼古丁联合使用纳入候选药物的评估。本项目旨在研究生物行为机制潜在的酒精和尼古丁使用和共同使用，并在两种动物模型中测试候选药物专为测试药物的酒精滥用，酒精和尼古丁的共同使用。第一模型使用了一个链式强化计划（CSR）过程，在这个过程中，搜索和消费都发生了在不同的环境线索和行为偶然性对环境影响的背景下，刺激对饮酒的驱动力和与慢性饮酒相关的行为的持续性。两个2匹配具有广泛自我饮酒史的NHP组（酒精组）或非酒精组将使用饮料（对照组）。第二种模式是新的酒精和尼古丁并发访问（ANCA）程序，其中口服酒精和IV尼古丁可同时用于自我给药。一功能评估组合提供药物副作用的评估。目标1将决定是否测试在持续饮酒的情况下，药物减少了CSR中的酒精寻求和自我给药，禁欲目标2将确定试验药物是否减少酒精和尼古丁自我管理在单一药物获取或ANCA程序下独立或同时进行。目标3将决定发病率测试药物的副作用。候选药物包括双功能和在OR亚型具有不同药理学特征的通用阿片受体（OR）配体， OR/伤害感受阿片肽（NOP）受体配体，大麻素成分大麻二酚（CBD），神经肽催产素和烟碱乙酰胆碱受体部分激动剂/拮抗剂伐尼克兰。Naltrexone 将作为阳性对照品和对照品进行试验。一种具有治疗潜力的药物将是一种减少线索保持寻求，并减少酒精自我管理，并具有低副作用。药物在酒精和尼古丁共同使用者中具有治疗潜力，将减少酒精自我给药，增加尼古丁的自我给药，并且理想地将减少两种药物的自我给药。一体化这些数据将提供有关行为和神经药理学机制的新信息，酒精滥用和酒精/尼古丁合用。不同模型的剂量效应函数和疗效比较可以为最佳剂量和治疗时机的治疗策略提供信息。这些信息最终将促进治疗酒精滥用和AUD的药物开发。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gut microbiome and metabolome in a non-human primate model of chronic excessive alcohol drinking.

DOI：
10.1038/s41398-021-01728-6
发表时间：
2021-12-01
期刊：
Translational psychiatry
影响因子：
6.8
作者：
Piacentino D;Grant-Beurmann S;Vizioli C;Li X;Moore CF;Ruiz-Rodado V;Lee MR;Joseph PV;Fraser CM;Weerts EM;Leggio L
通讯作者：
Leggio L

Effects of naltrexone on alcohol drinking patterns and extinction of alcohol seeking in baboons.