Modafinil and DRD4 Genotype in a Human Laboratory Model of Cocaine Relapse

描述（由申请人提供）：可卡因依赖治疗的特点是复发率高，但影响复发率的因素了解甚少。暴露于可卡因、压力和可卡因相关线索会增加可卡因渴望，多巴胺D4受体亚型（DRD4）的遗传多态性影响线索和药物暴露对渴望等级的影响。然而，渴望并不能有力地预测药物使用或复发。目前还没有数据描述DRD4多态性、线索和可卡因暴露在实际可卡因服用（即可卡因自我给药）中的相互作用。将复发测量纳入我们建立的实验室模型是药物开发的重要目标，因为可卡因自我给药模型在筛选可卡因依赖药物方面具有预测有效性。目标1：完善我们的可卡因自我给药程序，包括复吸措施。该模型以试点数据支持的假设为指导：复发的可能性和复发后自我服用可卡因的数量将随着以下因素而变化：(1)可卡因的成本，(2)与可卡因服用相关的上下文线索的存在，以及(3)非偶然的可卡因服用（即“启动”）。目的2：确定DRD4多态性对线索和可卡因诱导的复发的影响。与酒精相关的数据表明，具有7个或更多等位基因重复序列（DRD4L）的杂合或纯合个体比具有少于7个等位基因重复序列（drd4s）的个体表现出更多的线索和酒精诱导的渴望和更大的临床复发。我们假设，与DRD4 S组相比，可卡因依赖的DRD4 L志愿者将表现出更大的线索和启动诱导复发。目的3：测试莫达非尼对可卡因复发的影响，作为DRD4多态性的功能。我们假设莫达非尼将：(1)与安慰剂相比，降低线索和可卡因启动对复发可能性的影响；(2)如果开始使用可卡因，减少可卡因自我给药量；(3)DRD4 L组比DRD4 S组更有效地减少线索和可卡因诱导的复发。

DESCRIPTION (provided by applicant): Treatment for cocaine dependence is characterized by high rates of relapse, yet the factors influencing the likelihood of relapse are poorly understood. Exposure to cocaine, stress and cocaine-related cues increase cocaine craving, and genetic polymorphisms in the dopamine D4 receptor subtype (DRD4) influence the effects of cues and drug exposure on ratings of craving. However, craving does not robustly predict drug use or relapse. There are currently no data characterizing the interaction between DRD4 polymorphisms, cues and cocaine exposure on actual cocaine taking, i.e., cocaine self-administration. Incorporating measures of relapse into our established laboratory model is an important objective for medications development because models of cocaine self-administration have predictive validity in screening medications for cocaine dependence. Aim 1: Refine our cocaine self-administration procedures to include measures of relapse. The model is guided by hypotheses supported by pilot data: The likelihood of relapse and the quantity of cocaine self-administered following relapse will vary as a function of (1) the cost of cocaine, (2) the presence of contextual cues associated with cocaine-taking, and (3) noncontingent cocaine administration (i.e., 'priming'). Aim 2: Determine the influence of DRD4 polymorphisms on cue- and cocaine-induced relapse. Data with alcohol have demonstrated that individuals heterozygous or homozygous for 7 or more allele repeats (DRD4L) show increased cue- and alcohol-induced craving and greater relapse clinically than those with fewer than 7 allele repeats (DRD4 S). We hypothesize that cocaine-dependent DRD4 L volunteers will show greater cue- and prime-induced relapse compared to the DRD4 S group. Aim 3: Test the effects of modafinil on measures of cocaine relapse as a function of DRD4 polymorphisms. We hypothesize that modafinil will: (1) decrease the effect of both cues and a cocaine prime on the likelihood of relapse compared to placebo, (2) decrease the amount of cocaine self-administered if cocaine use is initiated, and (3) be more effective decreasing cue-and cocaine-induced relapse in the DRD4 L group than the DRD4 S group.