New Medication Treatments for Stimulant Dependence

描述（由申请人提供）：皮质-中脑边缘多巴胺（CM-DA）功能是可卡因强化的主要神经化学介质。5-羟色胺-3（5-HT 3）受体调节CM-DA功能。临床前研究表明，5-HT 3拮抗剂降低CM-DA受体介导的效应，包括过度运动。5-HT 3拮抗剂降低可卡因诱导的行为敏感性和耐受性，并减少自我给药，特别是在急性戒断状态下。在人类中，与对照组相比，昂丹司琼预处理的个体显示出增加的神经元活化和右脑血流量（rCBF）。综上所述，这是，因此，合理的假设，昂丹司琼可用于帮助恢复正常的多巴胺（DA）的功能，在最近从可卡因使用的戒断期，从而降低复发的可能性，一旦戒毒已经实现。人体实验室研究也表明，昂丹司琼减少了对精神兴奋剂的偏好，包括可卡因和安非他明。此外，在一项由NIDA资助的随机、双盲、初步研究（N = 16名受试者/组）中，检测昂丹司琼（0.25、1.0和4.0 mg b.i.d.）与安慰剂相比，我们表明昂丹司琼4 mg b.i.d.在增加每周无可卡因尿液样本的比例方面明显更有效。因此，人体实验室和初始临床数据为昂丹司琼是可卡因依赖的有效治疗提供了令人信服的证据。作为我们的假设的概念验证，我们建议建立昂丹司琼是否可以帮助减少或停止可卡因使用目前使用可卡因依赖的个人。我们将进行一项随机对照试验，受试者接受昂丹司琼（4 mg b.i.d.）或安慰剂（N = 100名受试者/组 * 2组= 200）作为标准化每周认知行为疗法（CBT）和短暂行为依从性增强治疗（BBCET）的辅助治疗，持续8周。我们的主要目的是检验我们假设的两个预测：1）昂丹司琼在增加每周无可卡因（禁欲）天数的比例方面上级安慰剂（通过自我报告的使用和可卡因主要代谢产物苯甲酰芽子碱的尿液分析进行评估），2）昂丹司琼在增加每周无可卡因尿液受试者的平均比例方面上级安慰剂。我们的第二个目的是测试：1）昂丹司琼在减少可卡因渴望方面是否上级安慰剂，这些可卡因渴望的减少将与可卡因摄入量的减少有关，2）昂丹司琼在改善心理社会功能和生活质量方面上级安慰剂，可卡因使用的具体减少转化为临床功能的普遍和可测量的改善。这项研究支持了一个新的研究者的工作，以解决NIDA的使命，开发安全有效的药物治疗可卡因依赖。

DESCRIPTION (provided by applicant): Cortico-mesolimbic dopamine (CM-DA) function is the primary neurochemical mediator of cocaine reinforcement. Serotonin-3 (5-HT3) receptors modulate CM-DA function. Preclinical studies show that 5-HT3 antagonists decrease CM-DA receptor-mediated effects, including hyperlocomotion. 5-HT3 antagonists decrease cocaine-induced behavioral sensitization and tolerance and decrease self-administration, particularly in acute withdrawal states. In humans, ondansetron-pretreated individuals compared with controls show increased neuronal activation and right cerebral blood flow (rCBF). Taken together, it is, therefore, reasonable to hypothesize that ondansetron can be used to aid the restoration of normative dopamine (DA) function during the period of recent withdrawal from cocaine use, thereby decreasing the potential for relapse to drug taking once abstinence has been achieved. Human laboratory studies also show that ondansetron reduces preference for psychostimulants, including cocaine and amphetamine. Further, in a NIDA-funded randomized, double-blind, pilot study (N = 16 subjects/group) to detect a therapeutic signal for ondansetron (0.25, 1.0, and 4.0 mg b.i.d.) vs. placebo, we showed that ondansetron 4 mg b.i.d. was significantly more efficacious at increasing the weekly proportion of cocaine-free urine specimens. Hence, human laboratory and initial clinical data provide compelling evidence for the proposition that ondansetron is an efficacious treatment for cocaine dependence. As a proof-of-concept of our hypothesis, we propose to establish whether ondansetron can aid in reducing or ceasing cocaine use among currently using cocaine dependent individuals. We will do a randomized controlled trial in which subjects receive either ondansetron (4 mg b.i.d.) or placebo (N = 100 subjects/group * 2 groups = 200) as an adjunct to standardized weekly cognitive behavioral therapy (CBT) and Brief Behavioral Compliance Enhancement Treatment (BBCET) for 8 weeks. Our primary aims are to test two predictions of our hypothesis: 1) ondansetron will be superior to placebo at increasing the weekly proportion of cocaine-free (abstinent) days (assessed by a combination of self-reported use and urine analysis for benzoylecgonine, the major metabolite of cocaine), and 2) ondansetron will be superior to placebo at increasing the weekly mean proportion of subjects with cocainefree urines. Our secondary aim is to test whether: 1) ondansetron will be superior to placebo at decreasing cocaine craving, and these reductions in cocaine craving will be associated with decreased cocaine intake, and 2) ondansetron is superior to placebo at improving psychosocial functioning and quality of life, and specific reductions in cocaine use translate to general and measurable improvements in clinical functioning. This study supports the work of a new investigator to address NIDA's mission to develop safe and efficacious medicines for the treatment of cocaine dependence.