Alpha Adrenergic Pharmacotherapy for Polydrug (Stimulant/Opiate) Abuse

描述（由申请人提供）：快球（海洛因/可卡因）成瘾是一个令人痛苦的公共卫生问题，目前还没有批准的药物。临床前证据表明，2肾上腺素能受体激动剂可以减少海洛因和可卡因在实验室动物中的成瘾相关作用，这表明它们也可能特别有效地减弱海洛因/可卡因“快球”组合的作用。PA 08-186要求研究开发多种药物成瘾的药物疗法，为了响应PA 08-186，我们建议在非人类药物成瘾转化模型中评估2种激动剂降低速球组合的滥用和复发相关效应的能力。首先，将使用药物鉴别和观察程序来为一系列新型β 2肾上腺素受体激动剂建立适当的时间和剂量参数，这些激动剂与FDA批准的药物可乐定相比，在β 2肾上腺素受体选择性方面不同，并且具有有利的副作用特征。这一信息将指导我们的研究，如何急性和慢性治疗2激动剂改变加强强度和摄入量的速度球组合使用的选择程序，合并同时可用的二阶时间表静脉注射药物注射和食物强化。药物成瘾的一个主要问题是，戒断个体的复发可能由各种刺激引发，包括暴露于药物，药物相关的线索或压力事件。为了解决这个问题，将进行单独的研究以确定2种激动剂如何改变快速球注射、快速球相关线索或压力刺激触发药物寻求行为的能力。最后，将对选定的2种肾上腺素能受体激动剂进行长期治疗研究，以确定在重复给药期间是否对选定的2种受体激动剂的镇静或其他可观察到的副作用产生耐受性。我们希望我们的研究能够确定2种激动剂，有效地减弱速度球自我管理的强化作用，并抑制复发相关触发因素对药物寻求的影响。这些发现将提供重要的临床前信息，以指导进一步开发2激动剂作为候选药物治疗快速球成瘾。

DESCRIPTION (provided by applicant): Speedball (heroin/cocaine) addiction is a distressing public health concern for which there currently is no approved medication. Preclinical evidence suggests that 2 adrenergic agonists may reduce addiction-related effects of heroin and cocaine in laboratory animals, suggesting that they also may be particularly effective in attenuating effects of heroin/cocaine 'speedball' combinations. In response to PA 08-186, which calls for research to develop pharmacotherapies for polydrug addiction, we propose to evaluate the ability of 2 agonists to reduce the abuse- and relapse-related effects of speedball combinations in nonhuman translational models of drug addiction. First, drug discrimination and observational procedures will be used to establish proper temporal and dosing parameters for a series of novel 2 agonists that differ in 2 adrenoceptor selectivity and have favorable side-effect profiles compared to the FDA-approved drug clonidine. This information will guide our studies of how acute and chronic treatment with 2 agonists alters the reinforcing strength and intake of speedball combinations using a choice procedure that incorporates concurrently available second-order schedule of i.v. drug injection and food reinforcement. A major problem in drug addiction is that relapse in abstinent individuals can be triggered by a variety of stimuli including exposure to drugs, drug-related cues, or stressful events. To address this problem, separate studies will be conducted to determine how 2 agonists modify the ability of speedball injections, speedball-associated cues, or stressful stimuli to trigger drug- seeking behavior. Finally, chronic treatment studies with selected 2 adrenergic agonists will be conducted to determine whether tolerance occurs to the sedative or other observable side-effects of selected 2 agonists during repeated administration. We expect our research to identify 2 agonists that effectively attenuate the reinforcing effects of speedball self-administration and inhibit the impact of relapse-related triggers to drug-seeking. These findings will provide essential preclinical information to guide further development of 2 agonists as candidate pharmacotherapeutics for speedball addiction.