Medications Development for Stimulant Abuse

描述（由申请人提供）：可卡因成瘾是一个重大的公共卫生问题，NIDA继续致力于研究可卡因成瘾的候选治疗方法的疗效和机制。在目前的资助期内，我们为越来越多的临床前和临床研究做出了贡献，这些研究表明，维持单胺释放剂d-安非他明可以减少可卡因的消耗。更具体地说，安非他明维持减少可卡因消耗的功效现已在啮齿动物、非人类灵长类动物、人类实验室研究和安慰剂对照双盲临床试验中得到证实。综上所述，这些发现提供了强有力的证据，证明安非他明维持作为一种“激动剂”方法对可卡因滥用治疗的有效性，类似于用阿片激动剂（如美沙酮、丁丙诺啡）治疗阿片成瘾或用尼古丁制剂（如尼古丁贴片）治疗烟草依赖。然而，安非他明维持治疗作为抗可卡因治疗的临床可行性受到安非他明本身的高滥用风险的限制，而且安非他明的抗可卡因作用是否可以从机制上与滥用相关的作用分离开来仍然是未知的。该应用程序旨在测试安非他明维持抗可卡因作用的机制，其结果可能为提高抗可卡因治疗的有效性和安全性提供新的策略。我们建议关注安非他明作用的潜在阿片机制，因为现有文献支持阿片机制在安非他明滥用相关作用中的作用，但阿片机制在安非他明抗可卡因作用中的作用尚不清楚。阿片受体家族包括µ、d和κ受体，以及最近发现的NOP （nociceptin/orphanin FQ）受体。目的是验证μ和d类阿片受体的激活，而不是κ或NOP受体的激活，是充分和必要的假设

DESCRIPTION (provided by applicant): Cocaine addiction is a significant public health problem, and NIDA remains committed to research on efficacy and mechanisms of candidate treatments for cocaine addiction. During the current funding period, we contributed to a growing body of preclinical and clinical research showing that cocaine consumption can be reduced by maintenance on the monoamine releaser d-amphetamine. More specifically, the efficacy of amphetamine maintenance to reduce cocaine consumption has now been demonstrated in rodents, nonhuman primates, human laboratory studies, and placebo-controlled double-blind clinical trials. Taken together, these findings provide strong evidence for efficacy of amphetamine maintenance as an "agonist" approach to cocaine abuse treatment that is analogous to treatment of opioid addiction with opioid agonists (e.g. methadone, buprenorphine) or of tobacco dependence with nicotine formulations (e.g. nicotine patch). However, the clinical viability of amphetamine maintenance as an anti-cocaine treatment is limited by amphetamine's own high abuse liability, and it remains unknown if the anti-cocaine effects of amphetamine can be mechanistically dissociated from its abuse-related effects. This application proposes to test mechanisms that underlie the anti-cocaine effects of amphetamine maintenance, and results could suggest new strategies to improve efficacy and safety of anti-cocaine treatments. We propose to focus on potential opioid mechanisms of amphetamine effects, because existing literature supports a role for opioid mechanisms in abuse-related amphetamine effects, but the role for opioid mechanisms in anti-cocaine effects of amphetamine is unknown. The opioid receptor family includes µ, d and κ receptors, as well as the more recently identified nociceptin/orphanin FQ (NOP) receptors. Aims are proposed to test the hypothesis that activation of µ and d opioid receptors, but not of κ or NOP receptors, is sufficient and necessary for anti-cocaine effects of amphetamine. Studies will feature an innovative cocaine-vs.-food choice procedure developed by this laboratory for use in nonhuman primates, and treatments will be administered chronically to promote translational relevance. The role of µ, d, κ and NOP receptors in abuse-related reinforcing and discriminative stimulus effects of amphetamine will also be tested for comparison to data on the role of these receptors in amphetamine's anti-cocaine effects. Results will clarify the relative role of opioid receptors in anti-cocaine vs. abue-related effects of amphetamine. This project will also provide new information on behavioral effects of NOP agonists and antagonists. Lastly, regardless of outcome, the project could have clinical relevance. For example, if opioid receptor activation IS sufficient and necessary, then novel opioid agonists could be targeted as stand-alone or adjunctive candidate anti-cocaine treatments. Alternatively, if opioid receptor activation IS NOT necessary for anti-cocaine effects, then opioid antagonists like naltrexone might be useful as adjuncts to reduce amphetamine abuse liability without impairing amphetamine's anti-cocaine effects.