Alpha Adrenergic Pharmacotherapy for Polydrug (Stimulant/Opiate) Abuse

描述(由申请人提供)：快球(海洛因/可卡因)成瘾是一个令人担忧的公共卫生问题，目前还没有批准的药物。临床前证据表明，两种肾上腺素能激动剂可能会减少海洛因和可卡因对实验动物的成瘾相关影响，这表明它们在减轻海洛因/可卡因“快速球”组合的影响方面也可能特别有效。为了响应PA 08-186，它呼吁研究开发治疗多药成瘾的药物，我们建议评估两种激动剂在非人类药物成瘾翻译模型中减少快速球组合滥用和复发相关影响的能力。首先，药物识别和观察程序将被用来为一系列新的2种激动剂建立适当的时间和剂量参数，这些激动剂在2种肾上腺素受体选择性上不同，并且与FDA批准的药物可乐定相比具有良好的副作用。这些信息将指导我们的研究，即两种激动剂的急性和慢性治疗如何改变快速球组合的加强强度和摄入量，使用合并同时可用的静脉注射二级程序的选择程序。注射药物和强化食物。吸毒成瘾的一个主要问题是，戒毒者的复发可以由各种刺激引发，包括接触毒品、与毒品有关的线索或应激事件。为了解决这个问题，将进行单独的研究，以确定两种激动剂如何改变快速球注射、与快速球相关的线索或应激刺激触发药物寻找行为的能力。最后，将对选定的两种肾上腺素能激动剂进行慢性治疗研究，以确定在重复给药期间，选定的两种激动剂是否对镇静剂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确定两种激动剂，它们能有效地减弱快速球自我给药的强化作用，并抑制与复发相关的触发因素对药物寻找的影响。这些发现将为进一步开发两种激动剂作为治疗快球成瘾的候选药物提供必要的临床前信息。

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.