Medication Development for Cocaine Dependence

可卡因依赖的药物开发

• 批准号: 6827173
• 负责人: Bankole A Johnson
• 金额: $ 62.4万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6827173
• 关键词: anticonvulsants; behavioral /social science research tag; clinical research; clinical trials; cocaine; cognitive behavior therapy; craving; drug abuse chemotherapy; drug addiction; drug addiction antagonist; drug adverse effect; drug design /synthesis /production; drug detection; drug screening /evaluation; gamma aminobutyrate; human subject; human therapy evaluation; interview; patient oriented research; psychosocial rehabilitation; reinforcer; urinalysis

DESCRIPTION (provided by applicant): Despite considerable scientific effort in the last two decades, no medication has proved to be an effective treatment for cocaine dependence. Cocaine's rewarding effects are mediated primarily through mesolimbic dopamine (DA) pathways. Yet, experiments that have focused on developing medications that either inhibit midbrain DA release or produce post-synaptic DA receptor blockade have shown that these are not effective treatments for cocaine dependence. Therefore, we propose to test a different strategy to developing a medication for treating cocaine dependence: Is opposition of midbrain DA release alone sufficient, or can we more reliably control DA effects by contemporaneously modulating DA functional expression? Expression of midbrain DA-associated reward may be mediated through inhibition of gamma-aminobutyric acid (GABA), via efferents that project from the nucleus accumbens to the cortex and that are themselves under the tonic control of excitatory amino acid (EAA) pathways. Thus, it is reasonable to hypothesize that a pharmacological agent that facilitates mesocortical GABAergic function and inhibits the action of EAAs should more reliably diminish cocaine's rewarding effects by inhibiting the expression of midbrain DA function in addition to decreasing midbrain DA release. The promise of this novel approach is exemplified by our recent proof-of-concept demonstration that topiramate (a fructo-pyranose derivative that diminishes DA functional expression) is effective at reducing craving and alcohol consumption among alcohol-dependent individuals. Next, we will expand the test of our hypothesis by determining in a randomized clinical trial (RCT) whether topiramate significantly reduces cocaine's rewarding effects associated with abuse liability. In this RCT, male and female cocaine dependent individuals will be randomized to receive either topiramate (up to 300 mg/day) or placebo (N = 90 subjects/group x 2 groups = 180) as an adjunct to standardized weekly Cognitive Behavioral Therapy for 12 weeks. Participants also will be followed up at 2 weeks and at 1,2, and 3 months after the end of the 12-week treatment period. The primary specific aims of this study are to test two predictions of our hypothesis: 1) Topiramate will be superior to placebo at increasing the maximum number of cocaine-free (abstinent) days (assessed by self-report of use and urine assays for benzoylecgonine, the major metabolite of cocaine), and 2) Topiramate will be superior to placebo at decreasing cocaine craving, and these reductions in cocaine craving will be associated with decreased cocaine intake. We also will test the additional secondary predictions that: 3) Topiramate, compared with placebo, will be associated with an improvement in psychosocial functioning as exemplified by: a) Improved general well-being; b) Social Functioning, and c) Enhanced Quality of Life, and d) that these improvements in psychosocial functioning will be correlated with decreased cocaine intake. This study supports NIDA's mission to develop effective medications for the treatment of cocaine dependence. It also will provide evidence for or against the above hypothesis, and thus will improve our understanding of the fundamental neurobiological mechanisms that control and modulate cocaine dependence.

描述（由申请人提供）：尽管在过去二十年中进行了大量的科学努力，但没有任何药物被证明可以有效治疗可卡因依赖。可卡因的奖励作用主要通过中脑边缘多巴胺 (DA) 途径介导。然而，专注于开发抑制中脑 DA 释放或产生突触后 DA 受体阻断药物的实验表明，这些药物并不是治疗可卡因依赖的有效方法。因此，我们建议测试一种不同的策略来开发治疗可卡因依赖的药物：单独抑制中脑 DA 释放是否足够，或者我们是否可以通过同时调节 DA 功能表达来更可靠地控制 DA 效应？中脑 DA 相关奖赏的表达可能是通过抑制 γ-氨基丁酸 (GABA) 来介导的，通过从伏核投射到皮质的传出神经，这些传出神经本身受到兴奋性氨基酸 (EAA) 途径的强直控制。因此，有理由推测，促进中皮质 GABA 能功能并抑制 EAA 作用的药物除了减少中脑 DA 释放外，还应通过抑制中脑 DA 功能的表达来更可靠地减少可卡因的奖赏效应。我们最近的概念验证证明了这种新方法的前景，即托吡酯（一种减少 DA 功能表达的吡喃果糖衍生物）可有效减少酒精依赖个体的渴望和饮酒量。接下来，我们将通过随机临床试验 (RCT) 确定托吡酯是否显着降低可卡因与滥用倾向相关的奖励效应，从而扩大对我们假设的检验。在这项随机对照试验中，男性和女性可卡因依赖者将随机接受托吡酯（最多 300 毫克/天）或安慰剂（N = 90 名受试者/组 x 2 组 = 180），作为标准化每周认知行为治疗的辅助治疗12周。 参与者还将在 12 周治疗期结束后 2 周以及 1、2 和 3 个月进行随访。本研究的主要具体目的是检验我们假设的两个预测：1) 在增加最大无可卡因（戒断）天数方面，托吡酯将优于安慰剂（通过使用自我报告和苯甲酰爱康宁尿液检测进行评估） ，可卡因的主要代谢物），以及 2）托吡酯在降低可卡因渴望方面优于安慰剂，并且可卡因渴望的这些降低将与可卡因渴望的降低相关随着可卡因摄入量的减少。我们还将测试额外的次要预测：3）与安慰剂相比，托吡酯将与心理社会功能的改善相关，例如：a）改善总体幸福感； b) 社会功能，c) 生活质量提高，以及 d) 心理社会功能的这些改善将与可卡因摄入量的减少相关。这项研究支持 NIDA 开发有效药物治疗可卡因依赖的使命。它还将为支持或反对上述假设提供证据，从而提高我们对控制和调节可卡因依赖的基本神经生物学机制的理解。