Human Laboratory Model of Cocaine Treatment: Behavioral Economic Analysis

描述(申请人提供)：背景：没有一种抗可卡因药物是普遍有效的，因为非药物因素，如环境条件(例如，药物使用的替代方案)和个人差异(例如，行为史)限制了任何药物的疗效。因此，可卡因药物的测试需要与行为治疗同步进行，并考虑到个体差异，以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体实验室模型中，我们将利用行为经济学分析来研究非药物阳性强化(“胡萝卜”；标准和奖品应急管理[CM]治疗的类似物)和惩罚(“大棒”；类似可卡因使用的不良后果)和治疗可卡因依赖的有前景的激动剂类药物(缓释d-苯丙胺[SR-AMP])的连续和间断方案改变可卡因需求的能力。我们还将前瞻性地探索两个个体差异因素，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(包括系统的复制和推广)，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，使用货币作为非药物替代品，确定：(A)高强度和低强度的持续正强化是否会增加可卡因弹性；(B)间歇性正强化条件(其大小将与持续强化等同)对可卡因弹性产生不同影响；以及(C)在由不同固定比率/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)毒品选择--或有金钱损失(相对于不惩罚)是否增加可卡因弹性，(B)较高或较低惩罚概率(相当于平均金钱损失幅度)增加可卡因弹性，以及(C)较高(相对于较低)正面强化和较高(相对于较低)惩罚概率组合额外地增加可卡因弹性。(3)确定SR-AMP 15毫克BID(30毫克/天)是否相对于安慰剂：(A)在最小辅助条件下(即低幅度非药物强化和不惩罚)增强可卡因弹性，以及(B)增强阳性强化/惩罚组合提高可卡因弹性的能力。第二个目的：确定实验前可卡因使用或戒断症状的个体差异是否缓和了积极强化或惩罚偶发事件对可卡因需求的效果。 公共卫生相关性：随着我们开发治疗可卡因依赖的药物，调查非药物因素(环境和个体差异)对药物疗效的影响程度至关重要。在这个可卡因治疗的人体实验室模型中，我们将利用行为经济学分析来程序化地检验非药物积极强化(金钱选择-或有收益)和惩罚(药物选择-或有金钱损失)与口服缓释D-苯丙胺(与安慰剂)相结合的连续和间歇性计划减少可卡因需求的能力。我们还将探索可卡因使用和戒断症状严重程度的个体差异是否会影响对这些影响的敏感性。三项专题综合和参数组织的研究(包括系统的复制和推广)旨在了解这些因素如何相互作用(短期目标)和提高可卡因依赖的治疗效果(长期目标)。

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).