New Medication Treatments for Stimulant Dependence

描述(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-HT3)受体调节CM-DA功能。临床前研究表明，5-HT3拮抗剂可降低CM-DA受体介导的效应，包括多动。5-HT3拮抗剂降低可卡因诱导的行为敏感化和耐受性，并减少自我给药，特别是在急性戒断状态下。在人类中，恩丹西酮预处理的患者与对照组相比，显示出神经元激活和右脑血流量(RCBF)增加。综上所述，恩丹西酮可以在最近戒除可卡因期间帮助恢复正常的多巴胺(DA)功能，从而降低戒毒后复发的可能性，因此是合理的假设。人体实验室研究还表明，恩丹西酮降低了人们对包括可卡因和苯丙胺在内的精神刺激剂的偏好。此外，在NIDA资助的一项随机、双盲、试点研究中(N=16名受试者/组)，以检测恩丹西酮(0.25、1.0和4.0 mg，b.i.d)的治疗信号。与安慰剂相比，我们显示恩丹西酮4毫克，每天两次。在增加每周无可卡因尿样比例方面明显更有效。因此，人体实验室和最初的临床数据为恩丹西酮是治疗可卡因依赖的有效方法这一命题提供了令人信服的证据。作为我们假设的概念验证，我们建议确定恩丹西酮是否有助于减少或停止目前使用可卡因依赖的个人的可卡因使用。我们将进行一项随机对照试验，受试者接受恩丹西酮(4 mg，每天2次)治疗。或安慰剂(N=100名受试者/组*2组=200人)，作为每周标准化认知行为治疗(CBT)和简短行为遵从性增强治疗(BBCET)的辅助，为期8周。我们的主要目的是检验我们假设的两个预测：1)恩丹西酮在增加每周无可卡因(禁欲)天数的比例方面优于安慰剂(通过自我报告使用和尿液分析可卡因的主要代谢物苯甲酰ecGonine进行评估)，以及2)恩丹西酮在增加尿可卡因患者每周平均比例方面优于安慰剂。我们的第二个目标是测试：1)恩丹西酮在减少可卡因渴求方面是否优于安慰剂，这些可卡因渴求的减少将与可卡因摄入量的减少相关；2)恩丹西酮在改善心理社会功能和生活质量方面优于安慰剂，而可卡因使用量的具体减少转化为临床功能的普遍和可测量的改善。这项研究支持了一位新的研究人员的工作，以实现NIDA开发安全有效的治疗可卡因依赖药物的使命。

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.