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

描述(申请人提供)：治疗可卡因依赖的特点是复发率高，但影响复发可能性的因素却知之甚少。暴露在可卡因、压力和与可卡因相关的线索中会增加对可卡因的渴望，而多巴胺D4受体亚型(DRD4)的基因多态性会影响线索和药物暴露对渴望程度的影响。然而，渴望并不能有力地预测吸毒或复发。目前还没有数据描述DRD4基因多态性、线索和可卡因暴露之间的相互作用对实际可卡因摄入的影响，即可卡因自我给药。将复发指标纳入我们已建立的实验室模型是药物开发的一个重要目标，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管理程序，将复发措施包括在内。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给药的可卡因数量将作为(1)可卡因的成本、(2)与吸食可卡因有关的背景线索的存在以及(3)非或有可卡因的给药(即“引爆”)的函数而变化。目的2：确定DRD4基因多态性对线索和可卡因诱导的复吸的影响。有关酒精的数据表明，等位基因重复数在7次或以上的个体(DRD4L)比等位基因重复数少于7次的个体(DRD4 S)表现出更高的线索和酒精诱发的渴求和更大的复发。我们假设，与DRD4 S组相比，可卡因依赖的DRD4 L志愿者将显示出更大的线索和主要诱导复发。目的3：测试莫达非尼对DRD4基因多态性对可卡因复吸率的影响。我们假设莫达非尼将：(1)与安慰剂相比，降低线索和可卡因原始剂对复发可能性的影响；(2)如果开始使用可卡因，则减少自身给药的可卡因数量；(3)在DRD4 L组中，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.