PHARMACOLOGICAL SUBSTRATES OF AMPHETAMINE ADDICTION

这项正在进行的研究的主要目标是评估多巴胺的作用。 D-苯丙胺对正常人的主观和行为影响(DA) 志愿者。这项研究的数据将与一项平行研究进行比较 多巴胺能预处理对d-氨基丁酸反应的影响 可卡因滥用者的苯丙胺，以及对尼古丁的反应 吸烟者。本研究将根据2(Agonist： D-苯丙胺[AMP]或安慰剂[PLAC])x 2(拮抗剂：氟哌啶醇[HAL] 或Plac)x 2(挑战药物：AMP或Plac)混合在-和之间 课题设计。前处理药物将是受试者内的 操纵，而挑战毒品的情况将在 研究对象。所有药物都将在双盲条件下使用， 条件的顺序平衡了不同的主题。每个人 受试者将参加每周一次的四次实验室会议。我们 假设氟哌啶醇和d-苯丙胺都会减弱 对挑战剂量的主观(例如，令人愉悦的)反应 安非他明，但联合氟哌啶醇和d- 安非他明将减弱对挑战剂量的反应 明显更大的程度。此外，我们预计合并后的 比前处理条件产生更好的副作用方案 无论是单独的预处理药。 对实验室动物的研究一直表明， 多巴胺(DA)在苯丙胺的作用中与其滥用有关，但要 目前尚无多巴胺能药物被证明有效治疗兴奋剂 虐待。多巴胺能药物疗效的缺乏可能与 与人类相比，DA在动物中的作用的差异 可测试的治疗药物剂量的限制。这 研究将直接解决这两个问题。我们将确定是否 多巴胺能激动剂和拮抗剂对大鼠肾上腺皮质激素反应的影响 人体中的苯丙胺表明DA在人类中扮演着重要的角色。在……里面 此外，我们将探索激动剂/拮抗剂组合的效果。 对安非他明的反应。到目前为止，DA激动剂和拮抗剂已经 对兴奋剂治疗所需剂量的耐受性不佳 成瘾；DA激动剂会产生令人不快的副作用，并可能 他们自己的滥用潜力，而DA拮抗剂是令人厌恶的，可以 长期使用后会产生持久持久的运动副作用。 基于之前对尼古丁激动剂/拮抗剂组合的工作和 戒烟，联合用药治疗有望有 更少的滥用责任，并产生比任何一种药物更少的副作用 单独，并应该阻止积极的奖励效果(例如，欣快感) D-苯丙胺。这种治疗方法的潜在用途 兴奋剂滥用不可低估，因为没有有效的 目前有治疗方法可用。

The primary goal of this ongoing study is to evaluate the role of dopamine (DA) in the subjective and behavioral effects of d-amphetamine in normal volunteers. Data from this study will be compared to a parallel study exploring the effects of dopaminergic pretreatments on responses to d- amphetamine in cocaine abusers, as well as on responses to nicotine in cigarette smokers. This study will be 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 will be a within- subjects manipulation, whereas the challenge drug condition will vary between subjects. All drugs will be administered under double-blind conditions, with the order of conditions counterbalanced across subjects. Each subject will attend four laboratory sessions, conducted once per week. We hypothesize that both haloperidol and d-amphetamine will attenuates subjective (e.g., euphorigenic) responses to the challenge dose of d- ampheatmine, 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. 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.