Preclinical Evaluation of Medications to Treat Polydrug Addiction

描述（由申请人提供）：这是响应NIDA计划公告PAS-08-186多药成瘾治疗药物开发的新申请。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，与重大公共健康问题有关，包括癌症、肺和心血管疾病以及艾滋病毒/艾滋病。我们开发了第一个可卡因+海洛因（快球）成瘾的临床前模型，现在我们建议开发一个新的可卡因+尼古丁滥用的多药模型。这两个模型将用于确定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药滥用是一个复杂的治疗挑战，并且通常无法从已知的药理学中预测药物的有效性。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FDA批准用于其他适应症的多种多样的药物。这些药物包括抗焦虑药、抗抑郁药、烟碱部分激动剂、兴奋剂和阿片类混合激动剂拮抗剂。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，海洛因或尼古丁单独滥用的相关影响。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。提出了经过充分验证的行为程序来评估这些药物对可卡因和可卡因+海洛因或尼古丁的多药组合的滥用相关效应的影响。药物鉴别程序将用于表征多种药物组合和候选治疗药物的效价、时程和刺激特征。在药物自我给药研究中，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，并监测可能的药物戒断症状时，停止治疗。将采用药物和食物维持反应的二阶时间表确定药物作用的选择性。最有效的药物的滥用倾向也将被检查。将使用一个累进比率程序来比较治疗药物的相对有效性以及多种药物组合的强化疗效改变的程度。这些多学科研究将促进将新型多药滥用药物转化为临床治疗。 公共卫生相关性：可卡因与海洛因或尼古丁混合使用的多种药物成瘾是一个严重的公共卫生问题，与癌症、心血管和肺部疾病以及艾滋病毒/艾滋病有关。我们建议在涉及可卡因+海洛因和可卡因+尼古丁的多药滥用临床前模型中评价临床上可用于治疗成瘾的其他适应症的药物的有效性。这一战略将有助于将最有效的治疗药物转化为临床试验。

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.