Preclinical Assessment of Medications for Alcohol Abuse

酒精是美国最广泛使用和滥用的毒品之一。迫切需要继续 改进AUD治疗，开发新药以减少酒精使用，并将尼古丁联合使用纳入 对候选药物的评估。该项目建议研究生物行为机制。 潜在的酒精和尼古丁的使用和联合使用，并在两个动物模型中测试候选药物 专门为测试酒精滥用以及酒精和尼古丁联合使用的药物而开发。第一 模型使用链式增援计划(CSR)过程，在CSR过程中发生寻求和消耗 在不同的环境线索和行为偶然性对环境的影响的背景下 对饮酒动力和与长期饮酒相关的行为的持续性的刺激。两个2匹配 有大量酒精自我给药史的NHP组(酒精组)或非酒精组 饮料(对照组)将被使用。第二种模式是一种新的酒精和尼古丁并发访问 (ANCA)口服酒精和静脉注射尼古丁同时用于自我给药的程序。一个 功能评估电池提供药物副作用的评估。目标1将决定测试是否 在持续饮酒和吸毒的情况下，毒品减少了CSR中的酒精寻求和自我给药 禁欲。目标2将确定测试药物是否减少酒精和尼古丁的自我给药 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 测试药物在功能评估电池中的副作用。候选药物包括双功能和 通用阿片受体(OR)配体在OR亚型上具有不同的药理特征 或/伤害性阿片肽(NOP)受体配体，大麻类成分大麻二醇(CBD)， 神经肽催产素和烟碱型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。一种具有治疗潜力的药物将会减少 线索-维持寻找，减少酒精自我给药，副作用较低。一种药物 在酒精和尼古丁有治疗潜力的情况下，共同吸毒者将减少酒精自我给药 增加尼古丁的自我给药，理想情况下会减少这两种药物的自我给药。整合 这些数据将提供有关行为和神经药理学机制的新信息 酗酒和酒精/尼古丁联合使用。不同模型间剂量效应函数和疗效的比较 可以为最佳剂量和治疗时机的治疗策略提供信息。这一信息最终将 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.