Preclinical Assessment of Medications for Alcohol Abuse

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。

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.