Preclinical Evaluation of Medications to Treat Polydrug Addiction

描述（由申请人提供）：这是响应NIDA项目公告PAS-08-186的新申请，用于多种药物成瘾治疗的药物开发。同时使用可卡因+海洛因和可卡因+尼古丁是多种药物滥用的普遍形式，并与严重的公共卫生问题有关，包括癌症、肺病和心血管疾病以及艾滋病毒/艾滋病。我们建立了第一个可卡因+海洛因（快球）成瘾的临床前模型，现在我们建议建立一个新的可卡因+尼古丁滥用的多药模型。这两种模型将用于识别和评估治疗可卡因与海洛因或尼古丁双重成瘾的药物。涉及两种或两种以上药物的多种药物滥用是一项复杂的治疗挑战，并且药物的有效性通常无法从其已知的药理学中预测。为了促进将最有效的治疗方法转化为临床实践，我们建议评估药理学上多样化的一系列药物，这些药物已被FDA批准用于其他适应症。这些药物包括抗焦虑药、抗抑郁药、尼古丁部分激动剂、兴奋剂和阿片类药物混合激动剂拮抗剂。在临床或临床前研究中，每种药物都被证明可以减少可卡因、海洛因或尼古丁的滥用相关影响。我们假设，有效减少可卡因自我给药的药物也可能有效减少可卡因与尼古丁或海洛因联合使用的滥用相关影响。提出了经过验证的行为程序来评估这些药物对可卡因和可卡因+海洛因或尼古丁多药组合的滥用相关影响的影响。药物鉴别程序将用于描述多药组合和候选治疗药物的效力、时间过程和刺激特征。在药物自我给药研究中，药物将长期给药以模拟临床治疗方案。慢性治疗是必要的，以确定药物作用的稳定性，任何不良副作用的严重程度和持续时间，并监测停止治疗时可能出现的药物戒断迹象。药物作用的选择性将由药物和食物维持反应的二级时间表决定。还将审查最有效药物的滥用责任。渐进比率程序将用于比较治疗药物的相对有效性以及多药联合增强疗效的改变程度。这些多学科研究将有助于将新型多药滥用药物转化为临床治疗。

DESCRIPTION (provided by applicant): This is a new application in response to NIDA Program Announcement PAS-08-186 for Medications Development for Polydrug Addiction Treatment. The concurrent use of cocaine + heroin and cocaine + nicotine are prevalent forms of polydrug abuse, and are associated with significant public health problems, including cancer, pulmonary and cardiovascular disease and HIV/AIDS. We developed the first preclinical model of cocaine + heroin (speedball) addiction, and now we propose to develop a new polydrug model of cocaine + nicotine abuse. These two models will be used to identify and evaluate medications for the treatment of dual addiction to cocaine in combination with heroin or nicotine. Polydrug abuse involving two or more drugs is a complex treatment challenge, and often the effectiveness of a medication is not predictable from its known pharmacology. To facilitate translation of the most effective treatment approaches into clinical practice, we propose to evaluate a pharmacologically diverse series of medications that are FDA approved for other indications. These medications include anxiolytics, antidepressants, nicotinic partial agonists, stimulants, and an opioid mixed agonist antagonist. Each medication has been shown to reduce the abuse-related effects of cocaine, heroin, or nicotine alone in clinical or preclinical studies. We hypothesize that medications that effectively reduce cocaine self-administration may also be effective in reducing the abuse-related effects of cocaine in combination with nicotine or heroin. Well-validated behavioral procedures are proposed to evaluate the effects of these medications on the abuse-related effects of cocaine and polydrug combinations of cocaine + heroin or nicotine. Drug discrimination procedures will be used to characterize the potency, time-course and stimulus characteristics of polydrug combinations, and candidate treatment medications. In drug self-administration studies, medications will be administered chronically to model clinical treatment programs. Chronic treatment is necessary to determine the stability of medication effects, the severity and duration of any adverse side effects, and to monitor possible medication withdrawal signs when treatment is discontinued. The selectivity of medication effects will be determined with a second-order schedule of drug- and food-maintained responding. The abuse liability of the most effective medications will also be examined. A progressive-ratio procedure will be used to compare the relative effectiveness of treatment medications as well as the extent to which the reinforcing efficacy of polydrug combinations is altered. These multi-disciplinary studies will facilitate translation of novel polydrug abuse medications into clinical treatment. PUBLIC HEALTH RELEVANCE: Polydrug addiction to cocaine in combination with heroin or nicotine is a significant public health problem associated with cancer, cardiovascular and pulmonary disorders and HIV/AIDS. We propose to evaluate the effectiveness of medications that are clinically available for other indications for treatment of addiction in preclinical models of polydrug abuse involving cocaine + heroin and cocaine + nicotine. This strategy will facilitate translation of the most effective treatment medications into clinical trials.