Rothman R B, Elmer G I, Shippenberg T S, Rea W, Baumann M H
Clinical Psychopharmacology Section, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Baltimore, Maryland 21224, USA.
Ann N Y Acad Sci. 1998 May 30;844:59-74.
Combined dopamine (DA) and 5-hydroxytryptamine (5-HT) releases such as phentermine (PHEN) and fenfluramine (FEN) are reported, in open label studies, to reduce craving for alcohol and cocaine and to prevent relapse. The objective of the studies reported here was to assess the actions of these agents alone and in combination in various animal models of drug addiction. Study 1. In vivo microdialysis experiments demonstrate that these agents preferentially release mesolimbic DA (PHEN) and 5-HT (FEN). Patients who relapse and use cocaine while taking these medications report diminished cocaine-like subjective effects. Microdialysis experiments were performed in awake rats, and dialysate samples were analyzed for DA and 5-HT. PHEN (1 mg/kg, intravenously (i.v.)) elevated DA (2-3-fold) for over 1.5 hr. Administration of cocaine (3 mg/kg, i.v.) increased DA 6-fold in saline-treated rats, but only 3-fold in PHEN-treated rats. PHEN did not reduce cocaine-induced increases in 5-HT. Study 2. These agents were assessed in a mouse model of cocaine-conditioned motoric activity (CCMA). Pretreatment with non-activating doses of PHEN (4.6 mg/kg, intraperitoneally (i.p.)) enhanced CCMA, whereas non-depressing doses of FEN (0.1 mg/kg, i.p.) did not alter CCMA or the PHEN-induced increase in CCMA. In contrast, sub-effective doses of FEN reduced CCMA stereotypy-like locomotion, whereas sub-effective doses of PHEN were without effect. PHEN reversed the FEN-induced increase in CCMA stereotypy-like locomotion. Study 3. PHEN and FEN were assessed in the conditional place preference model. FEN produced marked aversions for an environment previously associated with its administration and the minimum dose producing this effect was 3.0 mg/kg. In contrast, administration of PHEN, amphetamine (1.0-3.0 mg/kg) or morphine (3.0-5.0 mg/kg) produced dose-related preferences for the drug-paired place. However, the magnitude of the response to PHEN was less than that produced by the other prototypic drugs of abuse. In rats that received FEN (0.3 or 3.0 mg/kg) in combination with PHEN (3.0 mg/kg), the conditioned rewarding effects of PHEN were abolished. These data demonstrate that the rewarding effects of PHEN can be conditioned to stimuli previously associated with its administration. However, the conditioned response to this agent is less than that produced by prototypic drugs of abuse. The finding that PHEN-induced place preferences were attenuated by doses of FEN demonstrates that the combination of FEN/PHEN is devoid of motivational effects. The preclinical data obtained with PHEN/FEN in various models of drug provide a strong rationale for pursuing controlled clinical trials in humans with agents that act via a similar mechanism of action.
在开放标签研究中，有报告称联合使用多巴胺（DA）和5-羟色胺（5-HT）释放剂，如苯丁胺（PHEN）和芬氟拉明（FEN），可减少对酒精和可卡因的渴望并预防复发。本文报告的研究目的是评估这些药物单独及联合使用在各种药物成瘾动物模型中的作用。研究1. 体内微透析实验表明，这些药物优先释放中脑边缘多巴胺（PHEN）和5-羟色胺（FEN）。在服用这些药物时复发并使用可卡因的患者报告称，可卡因样主观效应有所减轻。在清醒大鼠中进行微透析实验，并对透析液样本进行多巴胺和5-羟色胺分析。苯丁胺（1毫克/千克，静脉注射（i.v.））使多巴胺升高（2至3倍）超过1.5小时。在生理盐水处理的大鼠中，注射可卡因（3毫克/千克，静脉注射）使多巴胺增加6倍，但在苯丁胺处理的大鼠中仅增加3倍。苯丁胺并未降低可卡因诱导的5-羟色胺增加。研究2. 在可卡因条件性运动活动（CCMA）小鼠模型中评估了这些药物。用非激活剂量的苯丁胺（4.6毫克/千克，腹腔注射（i.p.））预处理可增强CCMA，而无抑制作用剂量的芬氟拉明（0.1毫克/千克，腹腔注射）不会改变CCMA或苯丁胺诱导的CCMA增加。相反，亚有效剂量的芬氟拉明可降低CCMA刻板样运动，而亚有效剂量的苯丁胺则无此作用。苯丁胺可逆转芬氟拉明诱导的CCMA刻板样运动增加。研究3. 在条件性位置偏爱模型中评估了苯丁胺和芬氟拉明。芬氟拉明对先前与其给药相关的环境产生明显厌恶，产生这种效应的最小剂量为3.0毫克/千克。相比之下，给予苯丁胺、苯丙胺（1.0至3.0毫克/千克）或吗啡（3.0至5.0毫克/千克）会产生与药物配对位置相关的剂量依赖性偏爱。然而，对苯丁胺的反应强度小于其他典型滥用药物产生的反应。在接受芬氟拉明（0.3或3.0毫克/千克）与苯丁胺（3.0毫克/千克）联合使用的大鼠中，苯丁胺的条件性奖赏效应被消除。这些数据表明，苯丁胺的奖赏效应可与先前与其给药相关的刺激形成条件联系。然而，对该药物的条件反应小于典型滥用药物产生的反应。苯丁胺诱导的位置偏爱被芬氟拉明剂量减弱的发现表明，芬氟拉明/苯丁胺组合缺乏动机效应。在各种药物模型中用苯丁胺/芬氟拉明获得的临床前数据为在人类中对通过类似作用机制起作用的药物进行对照临床试验提供了有力依据。
