Alpha Adrenergic Pharmacotherapy for Polydrug (Stimulant/Opiate) Abuse

针对多种药物（兴奋剂/阿片类药物）滥用的α肾上腺素药物治疗

基本信息

批准号：
8086328
负责人：
JACK BERGMAN
金额：
$ 44.03万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8086328
关键词：
Abstinence Acute Address Adrenergic Agents Adrenergic Agonists Adrenergic Receptor Adverse effects Agonist Attenuated Behavior Chronic Clinical Clonidine Cocaine Cocaine Abuse Cocaine Dependence Cues Data Development Distress Dose Drug Addiction Drug Combinations Drug Metabolic Detoxication Drug usage Event Exhibits Exposure to FDA approved Food Goals Heroin Heroin Abuse Individual Injection of therapeutic agent Intake Investigation Laboratories Laboratory Animals Ligands Mediating Medical Modeling Monkeys Observational Study Opiates Opioid Pharmaceutical Preparations Pharmacotherapy Play Procedures Psychological reinforcement Public Health Recording of previous events Regimen Relapse Research Research Design Role Schedule Sedation procedure Self Administration Self-Administered Series Signs and Symptoms Stimulus Stress Stressful Event Testing Treatment Protocols Withdrawal addiction adrenergic base design disorder later incidence prevention drug abstinence drug discrimination drug seeking behavior effective therapy expectation lofexidine nonhuman primate noradrenergic novel opioid abuse pre-clinical prevent response sedative treatment strategy visual stimulus

项目摘要

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. PUBLIC HEALTH RELEVANCE: There is a clear medical need for new candidate medications to manage the Increasing dual heroin/cocaine ('speedball') abuse and addiction poses a grave public health problem for which no effective medications exist. Previous findings indicate that 2-adrenergic agonists can attenuate addiction-related effects of, separately, heroin and cocaine. We will address this public health problem of dual heroin/cocaine abuse and addiction by evaluating 2 adrenergic agonists as candidate pharmacotherapeutics to counteract 'speedball' abuse and aid in relapse prevention.

描述（由申请人提供）：快速球（海洛因/可卡因）成瘾是令人痛苦的公共健康问题，目前尚无批准的药物。临床前证据表明，2种肾上腺素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作用，这表明它们在减弱海洛因/可卡因“速度球”组合的影响方面也可能特别有效。为了响应PA 08-186，呼吁研究开发用于多药成瘾的药物疗法，我们建议评估2种激动剂减少非人类翻译模型的药物成瘾模型中降低滥用滥用和复发相关的作用的能力。首先，药物歧视和观察程序将用于为一系列新型2个激动剂建立适当的时间和给药参数，这些新型2个激动剂在2种adrenoceptor选择性方面有所不同，并且与FDA批准的药物可克洛尼定相比具有良好的副作用曲线。该信息将指导我们对使用2种激动剂进行急性和慢性治疗的研究，以使用选择程序，以同时可用的二阶时间表来改变速度球组合的增强强度和摄入速度。药物注射和食物加固。药物成瘾的一个主要问题是，避免个体的复发可能是由多种刺激引起的，包括暴露于药物，与药物相关的提示或压力性事件。为了解决这一问题，将进行单独的研究，以确定2种激动剂如何改变速球，速球相关的提示或压力刺激触发吸毒行为的能力。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会发生对选定的2种激动剂的镇静剂或其他可观察到的副作用。我们希望我们的研究能够确定2种激动剂，从而有效地减弱速度球自我给药的增强作用，并抑制与复发相关的触发因素对寻求药物的影响。这些发现将提供必不可少的临床前信息，以指导2种激动剂作为快速成瘾的候选药物治疗药的进一步发展。公共卫生相关性：明显的医疗需求需要新的候选药物来管理增加的双重海洛因/可卡因（'speedball'）虐待和成瘾带来了一个严重的公共卫生问题，不存在有效的药物。先前的发现表明，2-肾上腺素能激动剂可以分别减弱与成瘾相关的作用，即海洛因和可卡因。我们将通过评估2种肾上腺素能激动剂作为候选药物治疗药，以抵消“快球”的滥用并帮助预防复发，来解决双重海洛因/可卡因滥用和成瘾的公共卫生问题。