PHARMACOLOGICAL SUBSTRATES OF AMPHETAMINE ADDICTION

目的和方法：本研究的目的是：1)评价多巴胺(DA)在d-苯丙胺对正常志愿者的主观和行为效应中的作用；2)探讨DA激动剂和拮抗剂联合应用对苯丙胺奖赏的阻断作用。对实验室动物的研究表明，DA在调节安非他明的奖赏效应方面发挥了作用，但对人类的研究提供了不一致的结果。我们正在通过比较安慰剂、DA激动剂和DA拮抗剂对苯丙胺的主观和行为影响来探索DA的作用。我们还旨在确定与DA激动剂和拮抗剂联合预处理比单独使用任何一种治疗方法都能在多大程度上减少苯丙胺的影响，以努力扩大先前在吸烟者中的发现。研究按2(激动剂：D-苯丙胺[AMP]或安慰剂[PLAC])×2(拮抗剂：氟哌啶醇[HAL]或PLAC)×2(挑战药物：AMP或PLAC)在受试者内和受试者之间混合设计进行。前处理药物是受试者内部的操作，而挑战药物的情况因受试者而异。所有药物都是在双盲条件下给药，不同受试者的条件顺序是平衡的。我们假设氟哌啶醇和d-苯丙胺都将减弱对d-苯丙胺激发剂量的主观反应(例如，兴奋反应)，但联合使用氟哌啶醇和d-苯丙胺将在更大程度上减弱对激发剂量的反应。此外，我们预计联合的预处理条件将产生比单独使用任何一种预处理药物更好的副作用方案。结果：来自25名受试者的初步数据支持我们的假设。例如，安非他明和氟哌啶醇均可减弱对d-安非他明的兴奋反应；联合用药减弱反应的程度比单独用药的程度更大。此外，苯丙胺和氟哌啶醇可以相互抵消副作用。例如，氟哌啶醇导致精神运动能力略有下降，而安非他明的加入则逆转了这一点。这些初步结果表明，这种治疗方法值得进一步研究。意义和未来计划：对实验室动物的研究一直表明，多巴胺(DA)在苯丙胺(DA)滥用相关的苯丙胺效应中发挥了作用，但到目前为止，还没有多巴胺能药物被证明在治疗兴奋剂滥用方面有效。多巴胺能药物的疗效缺乏可能与DA在动物中的作用与人类相比有所不同，或者与可测试的治疗药物的剂量限制有关。这项研究将直接解决这两个问题。我们将确定多巴胺能激动剂和拮抗剂对人类苯丙胺反应的影响是否表明DA在人类中具有重要作用。此外，我们还将探讨激动剂/拮抗剂组合对苯丙胺反应的影响。到目前为止，DA激动剂和拮抗剂还不能很好地耐受到治疗兴奋剂成瘾所需的剂量；DA激动剂会产生令人不快的副作用，并可能本身就有滥用潜力；DA拮抗剂是令人厌恶的，长期使用后会产生长期和永久的运动副作用。根据以前对尼古丁激动剂/拮抗剂组合和戒烟的研究，联合药物治疗预计比任何一种药物单独使用的滥用可能性更小，产生的副作用更少，并应阻止d-苯丙胺的积极奖励作用(例如，欣快感)。由于目前还没有有效的治疗方法，因此不能低估这种治疗方法对兴奋剂滥用的潜在作用。如果这项研究的结果是有希望的，未来的研究将探索这些和其他多巴胺能治疗方法和组合在正常志愿者和被诊断为兴奋剂滥用和/或依赖的患者中的效果。

Purpose and Methods: The goals of this ongoing study are 1) to evaluate the role of dopamine (DA) in the subjective and behavioral effects of d-amphetamine in normal volunteers and 2) to explore the effects of the combined administration of a DA agonist and antagonist in blocking amphetamine reward. Studies with laboratory animals have demonstrated a role for DA in mediating the rewarding effects of amphetamine but studies with humans have provided inconsistent results. We are exploring the role of DA by comparing the subjective and behavioral effects of amphetamine after pretreatment with placebo, a DA agonist and a DA antagonist. We also aim to determine the extent to which combined pretreatment with a DA agonist and antagonist produces greated reduction of amphetamine's effects than either treatment alone, in an effort to extend previous findings in cigarette smokers. The study is conducted according to a 2 (Agonist: d-amphetamine [AMP] or placebo [PLAC]) x 2 (Antagonist: haloperidol [HAL] or PLAC) x 2 (Challenge drug: AMP or PLAC) mixed within- and between subjects design. The pretreatment drugs are within- subjects manipulations, whereas the challenge drug condition varies between subjects. All drugs are administered under double-blind conditions, with the order of conditions counterbalanced across subjects. We hypothesize that both haloperidol and d-amphetamine will attenuate subjective (e.g., euphorigenic) responses to the challenge dose of d-amphetamine, but that combined pretreatment with haloperidol and d-amphetamine will attenuate responses to the challenge dose to a significantly greater extent. Furthermore, we expect the combined pretreatment condition to produce a better side effects protocol than either pretreatment drug alone. Results: Preliminary data from 25 subjects supports our hypotheses. For example, pretreatment with both amphetamine and haloperidol attenuated euphorigenic responses to d- amphetamine; combined pretreatment attenuated responses to a greater extent than either pretreatment alone. Moreover, amphetamine and haloperidol offset the side effects of each other. For instance, haloperidol produced a slight decrement in psychomotor performance, which was reversed by the addition of amphetamine. These preliminary results suggest that this treatment approach should be studied further. Significance and future plans: Studies with laboratory animals have consistently demonstrated a role for dopamine (DA) in the effects of amphetamine related to its abuse, but to date no dopaminergic agents have proven effective in treating stimulant abuse. The lack of efficacy of dopaminergic agents may relate to differences in the role of DA in animals as compared to humans, or to limitations in the doses of the treatment drugs that can be tested. This study will directly address both issues. We will determine whether the effects of a dopaminergic agonist and antagonist on responses to amphetamine in humans suggest a significant role for DA in humans. In addition, we will explore the effects of an agonist/antagonist combination on responses to amphetamine. To date, DA agonists and antagonists have not been well tolerated at the doses required for treatment of stimulant addiction; DA agonists can produce unpleasant side effects and may have abuse potential of their own, and DA antagonists are aversive and can produce long lasting and permanent motor side effects after prolonged use. Based on previous work with nicotinic agonist/antagonist combinations and smoking cessation, the combined drug treatment would be expected to have less abuse liability and to produce fewer side effects than either drug alone, and should block the positive rewarding effects (e.g., euphoria) of d-amphetamine. The potential usefulness of this treatment approach for stimulant drug abuse cannot be underestimated since no effective treatments are available at this time. If the results of this study are promising, future studies will explore the effects of these and other dopaminergic treatments and combinations in both normal volunteers and in patients with diagnoses of stimulant abuse and/or dependence.