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

可卡因复吸人类实验室模型中的莫达非尼和 DRD4 基因型

• 批准号: 8075639
• 负责人: MARGARET HANEY
• 金额: $ 55.99万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8075639
• 关键词: Abstinence; Address; Affect; Alcohols; Alleles; Catechol O-Methyltransferase; Clinical; Clinical Data; Clinical Trials; Cocaine; Cocaine Dependence; Cocaine Users; Cues; DRD4 gene; Data; Development; Dose; Drug Exposure; Drug usage; Ecology; Environmental Risk Factor; Genes; Genetic; Genetic Polymorphism; Genotype; Human; Individual; Laboratories; Measures; Modafinil; Modeling; Patient Self-Report; Pharmaceutical Preparations; Placebos; Procedures; Relapse; Sampling; Screening procedure; Self Administration; Self-Administered; Smoke; Stress; Testing; Treatment outcome; alcohol cue; cocaine exposure; cocaine use; cost; craving; dopamine D4 receptor; dopamine transporter; drug relapse; fundamental research; non-drug; reinforcer; volunteer

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.

描述（由申请人提供）：可卡因依赖治疗的特点是复发率高，但影响复发可能性的因素却知之甚少。接触可卡因、压力和与可卡因相关的线索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评级的影响。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 多态性、线索和可卡因暴露与实际可卡因服用（即可卡因自我给药）之间的相互作用。将复发测量纳入我们建立的实验室模型中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，包括复发措施。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行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背景线索的存在，以及 (3) 非偶然的可卡因服用（即“启动”）。目标 2：确定 DRD4 多态性对提示和可卡因诱导的复发的影响。酒精数据表明，与少于 7 个等位基因重复 (DRD4 S) 的个体相比，具有 7 个或更多等位基因重复 (DRD4L) 的杂合或纯合个体表现出线索和酒精诱导的渴望增加，并且临床上复发率更高。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提示和启动诱导的复发。目标 3：测试莫达非尼对可卡因复吸的影响，作为 DRD4 多态性的函数。我们假设莫达非尼将：（1）与安慰剂相比，降低提示和可卡因初始剂对复发可能性的影响，（2）如果开始使用可卡因，则减少可卡因自我给药的量，以及（3）在 DRD4 L 组中比 DRD4 S 组更有效地减少提示和可卡因诱发的复发。