Effects of Oxytocin on the Human Abuse Liability of Methamphetamine

 描述(申请人提供)：甲基苯丙胺滥用和依赖是美国长期存在的公共卫生问题。到目前为止，FDA还没有批准任何药物来治疗甲基苯丙胺使用障碍。这项临床研究将在临床前研究的大力支持下，检验一种有前景的治疗甲基苯丙胺使用障碍的药物。最近，神经肽催产素被确定为甲基苯丙胺使用障碍药物治疗的有前景的候选药物。对啮齿动物的临床前研究发现，催产素通过减少甲基苯丙胺的自我给药、压力和药物启动的恢复以及条件性位置偏爱来降低甲基苯丙胺的增强效果(Carson等人，2010a；齐等人，2009年)。催产素还被证明可以减少甲基苯丙胺和可卡因引起的大鼠多动(Carson等人，2010a；qi等人，2009年；Kovacs等人，1990年；Sarnyai，1998)。拟议的临床研究利用这些发现来确定急性给予催产素对两种甲基苯丙胺剂量的人类滥用倾向的影响，这两种剂量的甲基苯丙胺在先前的人类行为药理学研究中被证明具有剂量依赖的滥用倾向效应(Hart等人，2002年)。在一项双盲、随机、受试者内、安慰剂对照设计中，18名健康的非寻求治疗兴奋剂的个体在接受甲基苯丙胺(口服10或20毫克)或安慰剂之前，将在6个疗程中接受催产素(24IU，鼻腔内注射)或安慰剂。措施将包括与滥用责任有关的甲基苯丙胺的受试者评级影响(例如，“嗜毒”)。我们假设催产素会降低受试者对两种甲基苯丙胺剂量的滥用责任评级。然而，由于在临床试验(Hart等人，2004；Hart等人，2007a，2007b；Bisaga等人，2006)中减少受试者评定的效果而不改变药物强化效果可能不能预测疗效，所以药物与金钱的选择程序(“多项选择程序”；Griffiths等人，1993)将在初始6个疗程的每一次中确定药物强化效果。也就是说，每个参与者将做出一系列选择，是再次接受在那次治疗中使用的药物(S)，还是接受不同数额的钱。在6个疗程中的药物与金钱选择中，将随机选择一个在第7个疗程中提供。如果偏爱的是钱，那么在第七次治疗中，参与者将在未盲目的鼻腔和口服安慰剂之外获得该金额。我们假设，与安慰剂相比，催产素会降低两种剂量的甲基苯丙胺的强化效果(即货币价值)。这项研究将确定是否应该投入更多的资源来开发催产素作为一种甲基苯丙胺使用障碍药物，包括对寻求治疗的甲基苯丙胺依赖者进行临床试验。因此，这项研究可能大大推进甲基苯丙胺使用障碍的药物治疗领域。

 DESCRIPTION (provided by applicant): Methamphetamine abuse and dependence are persistent public health issues in the United States. To date, no medications have been approved by the FDA for the treatment of methamphetamine use disorders. This clinical study will examine a promising medication for methamphetamine use disorders with strong support from preclinical research. Recently, the neuropeptide oxytocin has been identified as a promising candidate for methamphetamine use disorder pharmacotherapy. Preclinical studies with rodents have found that oxytocin decreases the reinforcing efficacy of methamphetamine by reducing methamphetamine self-administration, stress- and drug-primed reinstatement, and conditioned place preference (Carson et al., 2010a; Qi et al., 2009). Oxytocin has also been shown to decrease hyperactivity induced by methamphetamine and cocaine in rats (Carson et al., 2010a; Qi et al., 2009; Kovacs et al., 1990; Sarnyai, 1998). The proposed clinical study draws on these findings to determine the effects of acute oxytocin administration on the human abuse liability of two methamphetamine doses shown to have dose-dependent abuse-liability effects in previous human behavioral pharmacology research (Hart et al., 2002). In a double-blind, randomized, within-subject, placebo- controlled design, 18 healthy non-treatment seeking stimulant using individuals will be administered either oxytocin (24 IU, intranasal) or placebo prior to receiving methamphetamine (10 or 20 mg, oral) or placebo across 6 sessions. Measures will include abuse-liability related subject-rated effects of methamphetamine (e.g., "drug liking"). We hypothesize that oxytocin will decrease subject-rated abuse liability ratings fo both methamphetamine doses. However, because a reduction in subject-rated effects without a change in drug reinforcement may not predict efficacy in clinical trials (Hart et al., 2004; Hart e al., 2007a, 2007b; Bisaga et al., 2006), a drug vs. money choice procedure (the "multiple-choice procedure"; Griffiths et al., 1993) will determine drug reinforcement effects in each of the initia 6 sessions. That is, each participant will make a series of choices between receiving the drug(s) administered on that session once again vs. receiving various amounts of money. One of the drug vs. money choices across the 6 sessions will be randomly selected to be delivered in a 7th session. If the preference was money, then in the 7th session the participant would receive that amount in addition to unblinded intranasal and oral placebos. We hypothesize that, relative to placebo, oxytocin will decrease the reinforcer efficacy (i.e., monetary value) of both methamphetamine doses. The study will determine if larger resources should be devoted to developing oxytocin as a methamphetamine use disorder medication, including clinical trials in treatment-seeking methamphetamine-dependent individuals. This study may therefore substantially advance the field of pharmacotherapy for methamphetamine use disorders.