Development of Guanfacine to decrease drug craving, anxiety and cocaine relapse r

描述（由申请人提供）：本申请拟进行一项随机、双盲、安慰剂对照的实验室研究，以检验胍法辛（GUA）是否能降低可卡因依赖、尼古丁吸烟（CD）个体对可卡因和尼古丁的渴望、焦虑和压力相关的唤醒。在之前的研究中，我们已经表明，实验室暴露于压力和药物线索会增加对药物的渴望和压力相关的唤醒，这两种方法都能预测可卡因复发的结果。α -2肾上腺素能激动剂如洛非昔定和胍法辛可减弱应激诱导的可卡因寻求行为在有可卡因经验的实验动物中的恢复。在之前的初步研究中，我们已经表明，洛非昔定可以减少压力和线索诱导的阿片类药物和可卡因的渴望，并减少服用纳曲酮的阿片类药物依赖个体的负面影响和生理唤醒。它也被发现提高阿片戒断率和依从每日纳曲酮方案。初步研究表明，与安慰剂（PLA）相比，每日给药2毫克和3毫克的GUA在药物线索诱导和压力诱导的药物渴望、焦虑和压力相关唤醒方面有积极的结果。因此，根据之前的临床前研究和我们的临床发现，我们提出了一项为期3年的研究，将招募60名CD患者参加一项随机、双盲、安慰剂对照的为期4周的住院实验室研究。研究的具体目的如下：(1)评估CD患者每日服用胍法辛2mg和3mg的安全性/耐受性；(2)确定胍法辛对住院期间每周评估的基础可卡因和尼古丁渴望、抑郁症状和感知压力评分的剂量依赖性；(3)确定胍法辛对应激、药物提示和应激+药物联合提示情景下引导意象暴露后可卡因渴望、尼古丁渴望和情绪的剂量依赖性；(4)确定胍法辛对应激、药物提示和应激+药物联合提示情景下心血管和儿茶酚胺（去甲肾上腺素和肾上腺素）反应的剂量依赖性。这项研究的结果将提供重要的信息，说明α -2肾上腺素能化合物如胍法辛是否有希望减少药物渴望、焦虑和压力，这些因素被证明是预测高可卡因复发结果的因素。如果提出的假设得到支持，它也将为进一步开发胍法辛作为预防可卡因复发的药物提供证据。

DESCRIPTION (provided by applicant): This application proposes to conduct a randomized, double blind, placebo-controlled laboratory study to examine whether guanfacine (GUA) decreases cocaine and nicotine craving, anxiety and stress related arousal in cocaine dependent, nicotine smoking (CD) individuals. In previous research we've shown that laboratory exposure to stress and drug cues increases drug craving and stress related arousal and both measures predict cocaine relapse outcomes. Alpha-2-adrenergic agonists such as lofexidine and guanfacine attenuate stress-induced reinstatement of cocaine-seeking behavior in cocaine experienced laboratory animals. In previous pilot studies, we've shown that lofexidine decreases stress and cue-induced opiate and cocaine craving and reduces negative affect and physiological arousal in opiate dependent individuals treated with naltrexone. It was also found to improve opiate abstinence rates and compliance with daily naltrexone regimen. Preliminary work with GUA 2 mg and 3 mg daily dosing versus placebo (PLA) showed positive results with respect to drug cue-induced and stress- induced drug craving, anxiety and stress-related arousal. Thus, in light of previous preclinical research and our clinical findings, we propose a 3-year study that will recruit 60 CD individuals to participate in a randomized, double blind, placebo-controlled 4-week inpatient laboratory study. The following specific aims will be addressed: (1) to evaluate the safety/tolerability of 2mg and 3mg daily of guanfacine in CD individuals; (2) to determine the dose-dependent effects of guanfacine on basal cocaine and nicotine craving, depressive symptoms and perceived stress scores in weekly assessments during the inpatient stay; (3) To determine the dose-dependent effects of guanfacine on cocaine craving, nicotine craving and mood following guided imagery exposure to stress, drug cue and combined stress+drug cue scenarios; and (4) to determine the dose-dependent effects of guanfacine on cardiovascular and catecholamine (norepinephrine and epinephrine) response following exposure to stress, drug cue and combined stress+drug cue scenarios. Findings from this study will provide important information on whether alpha-2adrenergic compounds such as guanfacine show promise in decreasing drug craving, anxiety and stress, factors shown to predict high cocaine relapse outcomes. If the proposed hypotheses are supported, it will also provide evidence for further development of guanfacine as a medication for cocaine relapse prevention. PUBLIC HEALTH RELEVANCE: Drug craving and associated high cocaine relapse rates are major clinical challenges in the treatment of cocaine dependence, and drug craving, anxiety and stress-related arousal are significant factors that increase cocaine relapse risk. The proposed study will test guanfacine as a potential therapeutic strategy to decrease these symptoms of drug craving, anxiety and distress and cocaine relapse risk and the results will have significant clinical implications for the development of new medications to decrease cocaine craving and prevent relapse in cocaine dependence.