Human Laboratory Model of Cocaine Treatment: Behavioral Economic Analysis

背景：没有抗可卡因药物是普遍有效的，因为非药物因素，如环境条件（如替代药物使用）和个体差异（如行为史）限制了任何药物的疗效。因此，可卡因药物试验需要与行为疗法同时进行，同时考虑到个体差异，以便了解相互作用的机制和药物疗效的潜在边界条件。方法：在这个可卡因治疗的人类实验室模型中，我们将研究非药物正强化（“胡萝卜”，类似于标准和基于奖励的应急管理[CM]治疗）和惩罚(“棍棒”；一种治疗可卡因依赖的激动剂样药物（缓释d-安非他明[SR-AMP]），使用行为经济学分析来改变可卡因需求。我们还将前瞻性地探讨两个个体差异因素，可卡因使用水平和可卡因戒断症状的严重程度，这可能会影响对这些影响的敏感性。通过进行主题整合和参数组织的研究（包括系统重复和扩展），我们希望了解这些因素如何相互作用（短期目标），并最终提高可卡因依赖的治疗效果（长期目标）。主要目的：(1)在CM的实验室模型中，使用金钱作为非药物替代品，确定：(a)高强度与低强度的连续正强化是否会增加可卡因的弹性；(b)间歇性正强化条件（其强度将等同于连续强化）对可卡因弹性的影响不同；(c)在由不同固定比例/单位剂量组合组成的匹配单价下，可卡因需求在功能上是相等的，(2)确定(a)药物选择-或有金钱损失（可预测的惩罚，相对于没有惩罚）是否会增加可卡因弹性，(b)更高的惩罚概率与更低的惩罚概率（等同于金钱损失的平均幅度）是否会增加可卡因弹性，(c)较高（相对于较低）强度的正强化和较高（相对于较低）惩罚概率的组合会增加可卡因弹性。(3)确定SR-AMP 15mg BID（总30mg /天）相对于安慰剂是否：(a)在最低辅助条件下（即低强度非药物强化和无惩罚）增加可卡因弹性，以及(b)增强正强化/惩罚组合增加可卡因弹性的能力。次要目的：确定实验前可卡因使用或戒断症状的个体差异是否会调节正强化或惩罚偶然性对可卡因需求的影响。

DESCRIPTION (provided by applicant): Background: No anti-cocaine medication will be universally effective because non-medication factors such as environmental conditions (e.g. alternatives to drug use) and individual differences (e.g. behavioral history) constrain the efficacy of any medication. Therefore, tests of cocaine medications need to be conducted in synchrony with behavior therapies also taking into account individual differences in order to understand the mechanisms of interaction and potential boundary conditions of a medication's efficacy. Approach: In this human laboratory model of cocaine treatment, we will investigate the ability of continuous and intermittent schedules of non-drug positive reinforcement ("Carrots"; analogues of standard and prize-based contingency management [CM] treatment) and punishment ("Sticks"; analogue of the adverse consequences of cocaine use) and a promising agonist-like medication for treatment of cocaine dependence (sustained release d- amphetamine [SR-AMP]) to alter cocaine demand using behavioral economic analyses. We will also prospectively explore two individual difference factors, level of cocaine use and severity of cocaine withdrawal symptoms, which may influence sensitivity to these effects. By conducting thematically integrated and parametrically organized studies (including systematic replications and extensions), we hope to understand how these factors interact (short term goal) and ultimately improve treatment efficacy for cocaine dependence (long term goal). Primary Aims: (1) Determine in a laboratory model of CM, using money as a non-drug alternative, whether: (a) higher- vs. lower-magnitude continuous positive reinforcement increases cocaine elasticity; (b) intermittent positive reinforcement conditions (which will be equated in magnitude with continuous reinforcement) differentially affect cocaine elasticity; and (c) cocaine demand is functionally equivalent at matched unit prices comprised of differing fixed ratio/unit dose combinations, (2) Determine whether (a) drug choice-contingent money loss (predictable punishment, relative to no punishment) increases cocaine elasticity, (b) higher vs. lower probabilities of punishment (equated for average magnitude of money loss) increase cocaine elasticity, and (c) the combination of higher (relative to lower) magnitude positive reinforcement and higher (relative to lower) probability of punishment additively increases cocaine elasticity. (3) Determine whether SR-AMP 15 mg BID (30 mg/day total) relative to placebo: (a) increases cocaine elasticity under minimally assisted conditions (i.e. low-magnitude non-drug reinforcement and absence of punishment), and (b) enhances the ability of positive reinforcement/punishment combinations to increase cocaine elasticity. Secondary Aim: Determine whether pre-experimental individual differences in cocaine use or withdrawal symptoms moderate the efficacy of positive reinforcement or punishment contingencies on cocaine demand. PUBLIC HEALTH RELEVANCE: As we develop medications for cocaine dependence, it is critical to investigate the extent to which non-drug (environmental and individual difference) factors influence medication efficacy. In this human laboratory model of cocaine treatment, we will programmatically examine the ability of continuous and intermittent schedules of non-drug positive reinforcement (money choice-contingent earnings) and punishment (drug choice-contingent money loss), in combination with oral sustained release d-amphetamine (vs. placebo), for reducing cocaine demand using behavioral economic analyses. We will also explore whether individual differences in cocaine use and withdrawal symptom severity influence sensitivity to these effects. Three thematically integrated and parametrically organized studies (including systematic replications and extensions) are intended to understand how these factors interact (short term goal) and to improve treatment efficacy for cocaine dependence (long term goal).