Alpha Adrenergic Pharmacotherapy for Polydrug (Stimulant/Opiate) Abuse

描述（由申请人提供）：速球（海洛因/可卡因）成瘾是一种令人痛苦的公共卫生问题，目前没有批准的药物。临床前证据表明，2种肾上腺素能激动剂可以减少实验动物对海洛因和可卡因的成瘾相关影响，这表明它们在减弱海洛因/可卡因“速球”组合的影响方面也可能特别有效。pa08 -186要求研究开发多种药物成瘾的药物治疗方法，为了响应这一要求，我们建议在药物成瘾的非人类翻译模型中评估两种激动剂减少快速球联合药物滥用和复发相关效应的能力。首先，药物鉴别和观察程序将用于建立适当的时间和剂量参数，用于一系列新的激动剂，这些激动剂与fda批准的药物可乐定相比，在两种肾上腺素能受体的选择性上有所不同，并且具有良好的副作用。这一信息将指导我们的研究，即使用两种激动剂的急慢性治疗如何改变加速球组合的强化强度和摄入量，选择程序包括同时使用静脉注射药物和食物强化的二级计划。药物成瘾的一个主要问题是，戒断个体的复发可能由多种刺激触发，包括接触药物、药物相关线索或压力事件。为了解决这个问题，将进行单独的研究，以确定两种激动剂如何改变快速球注射、快速球相关提示或压力刺激触发药物寻求行为的能力。最后，将对选定的2种肾上腺素能激动剂进行慢性治疗研究，以确定在重复给药过程中是否对选定的2种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两种激动剂，它们可以有效地减弱快速球自我给药的强化作用，并抑制复发相关触发因素对药物寻找的影响。这些发现将提供必要的临床前信息，指导进一步开发两种激动剂作为治疗快球成瘾的候选药物。

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.