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：
8461926
负责人：
JACK BERGMAN
金额：
$ 40.26万
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 2016-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8461926
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.

描述（由申请人提供）：快速球（海洛因/可卡因）成瘾是一个令人痛苦的公共健康问题，目前尚无批准的药物治疗。临床前证据表明，2 种肾上腺素能激动剂可能会减少实验动物中海洛因和可卡因成瘾相关的影响，这表明它们在减弱海洛因/可卡因“快速球”组合的影响方面也可能特别有效。 PA 08-186 呼吁研究开发针对多种药物成瘾的药物疗法，为了响应这一要求，我们建议评估 2 种激动剂在非人类药物成瘾转化模型中减少速球组合滥用和复发相关影响的能力。首先，将使用药物区分和观察程序来为一系列新型 2 激动剂建立适当的时间和剂量参数，这些激动剂的 2 肾上腺素受体选择性不同，并且与 FDA 批准的药物可乐定相比具有有利的副作用特征。该信息将指导我们研究使用 2 种激动剂进行急性和慢性治疗如何改变快速球组合的增强强度和摄入量，使用选择程序，该程序结合了同时可用的静脉注射二阶时间表。药物注射和食物强化。吸毒成瘾的一个主要问题是，戒毒者的复吸可能是由各种刺激引发的，包括接触毒品、与毒品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 种激动剂如何改变速度球注射、速度球相关线索或压力刺激触发寻药行为的能力。最后，将使用选定的2种肾上腺素能激动剂进行长期治疗研究，以确定在重复给药期间是否出现对选定的2种激动剂的镇静作用或其他可观察到的副作用的耐受性。我们希望我们的研究能够确定 2 种激动剂，它们可以有效减弱快速球自我给药的增强作用，并抑制与复发相关的触发因素对药物寻求的影响。这些发现将为指导 2 激动剂作为快速球成瘾候选药物治疗的进一步开发提供重要的临床前信息。