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）：可卡因依赖性治疗的特征是复发率高，但是影响复发可能性的因素却鲜为人知。接触可卡因，应激和与可卡因相关的提示增加了可卡因的渴望，多巴胺D4受体亚型（DRD4）中的遗传多态性会影响提示和药物暴露对渴望等级的影响。但是，渴望并不能强烈预测药物使用或复发。当前，尚无表征DRD4多态性，提示和可卡因在实际可卡因（即可卡因自我给药）上的相互作用的数据。将复发度量纳入我们已建立的实验室模型是药物开发的重要目标，因为可卡因自我管理模型在筛查可卡因依赖性药物方面具有预测的有效性。目标1：完善我们的可卡因自我管理程序，以包括复发措施。该模型由试验数据支持的假设引导：复发的可能性和复发后自我管理的可卡因数量将因（1）可卡因的成本而异，（2）存在与可卡因摄入的上下文提示，以及与可卡因摄取的生产相关的，以及（3）非企业可卡因可卡因管理局（3） AIM 2：确定DRD4多态性对提示和可卡因诱导的复发的影响。酒精的数据表明，比少于7个等位基因重复序列（DRD4 s）的人（DRD4L）重复7或更多等位基因重复（DRD4L）的个体表明提示和酒精引起的渴望和更大的复发性（DRD4 s）增加。我们假设与DRD4 S组相比，可卡因依赖性的DRD4 L志愿者将显示出更大的提示和原始诱导的复发。 AIM 3：测试莫达非尼对可卡因复发量的影响，与DRD4多态性的关系。我们假设莫达非尼将：（1）与安慰剂相比，提示和可卡因素的影响对复发的可能性降低，（2）如果启动可卡因使用的可卡因自我管理的量，则（3）比drdd4 l d dredd4 l d drdd4 l d drd d drd d d d d d d d d d d d d d d d drd d d d d d d drd d d drd d d d d d d d d d d dred d dred s ldd s ldd s ldd s。