Effects of Oxytocin on the Human Abuse Liability of Methamphetamine

 描述（由申请人提供）：甲基苯丙胺滥用和依赖是美国持续存在的公共卫生问题。迄今为止，FDA尚未批准任何药物用于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有力支持下，研究一种有前途的甲基苯丙胺使用障碍药物。最近，神经肽催产素已被确定为甲基苯丙胺使用障碍药物治疗的一个有前途的候选人。对啮齿动物的临床前研究已经发现，催产素通过减少甲基苯丙胺自我给药、应激和药物引发的恢复以及条件性位置偏好来降低甲基苯丙胺的增强功效（卡森等人，2010 a; Qi等人，2009年）。催产素还显示出减少大鼠中由甲基苯丙胺和可卡因诱导的活动过度（卡森等人，2010 a; Qi等人，2009; Kovacs等人，1990; Sarnyai，1998）。所提出的临床研究利用这些发现来确定急性催产素施用对两种甲基苯丙胺剂量的人类滥用倾向的影响，所述两种甲基苯丙胺剂量在先前的人类行为药理学研究中显示具有剂量依赖性滥用倾向效应（哈特等人，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的兴奋剂使用者将在接受甲基苯丙胺（10或20 mg，口服）或安慰剂之前，在6个疗程中给予催产素（24 IU，鼻内）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，“药物喜好”）。我们假设催产素会降低两种甲基苯丙胺剂量的受试者滥用倾向评级。然而，由于受试者评定效应的降低而不改变药物强化可能不能预测临床试验中的功效（哈特等人，2004;哈特等人，2007 a，2007 b; Bisaga等人，2006），药物与金钱选择程序（“多项选择程序”; Griffiths等人，1993年）将确定药物强化的影响，在每一个第六届会议。也就是说，每个参与者将在再次接受该疗程中给予的药物与接受各种金额之间做出一系列选择。在6个疗程中，将随机选择一个药物与金钱的选择，在第7个疗程中进行。如果偏好是金钱，则在第7阶段，受试者将接受该金额以及非盲态鼻内和口服安慰剂。我们假设，相对于安慰剂，催产素会降低催产素的疗效（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甲基苯丙胺使用障碍药物，包括在寻求治疗的甲基苯丙胺依赖者中进行临床试验。因此，这项研究可能会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.