Medication Development for Cocaine Dependence

描述(申请人提供)：尽管在过去的二十年里做出了相当大的科学努力，但没有一种药物被证明是治疗可卡因依赖的有效方法。可卡因的奖赏效应主要是通过中脑边缘多巴胺(DA)途径介导的。然而，专注于开发抑制中脑DA释放或产生突触后DA受体阻断的药物的实验表明，这些都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，以开发一种治疗可卡因依赖的药物：仅反对中脑DA释放就足够了，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)，通过从伏核投射到皮质的传出神经，本身受兴奋性氨基酸(EAA)通路的紧张性控制而介导的。因此，有理由假设，一种促进中皮质GABA能功能并抑制EaAs作用的药物，除了减少中脑DA的释放外，还应通过抑制中脑DA功能的表达来更可靠地减弱可卡因的奖赏效应。我们最近的概念验证证明，托吡酯(一种减少DA功能表达的果糖衍生物)在减少酒精依赖者的渴望和酒精消费方面是有效的，这一新方法的前景就是例证。接下来，我们将通过在一项随机临床试验(RCT)中确定托吡酯是否显著降低可卡因与滥用倾向相关的奖励效应，来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(每天最多300毫克)或安慰剂(N=90名受试者/组×2组=180人)，作为标准化每周认知行为疗法的辅助治疗，为期12周。 参与者还将在2周以及12周治疗期结束后的1、2和3个月进行随访。这项研究的主要目的是检验我们假设的两个预测：1)托吡酯在增加可卡因的最大无(戒断)天数方面优于安慰剂(通过自我报告可卡因的主要代谢物苯甲酰ecGonine的使用情况和尿液检测来评估)，以及2)托吡酯在减少可卡因渴望方面优于安慰剂，并且这些可卡因渴望的减少将与可卡因摄入量的减少相关。我们还将测试额外的二级预测：3)与安慰剂相比，托吡酯将与心理社会功能的改善有关，例如：a)总体幸福感的改善；b)社会功能的改善，以及c)生活质量的提高，以及d)心理社会功能的改善将与可卡因摄入量的减少相关。这项研究支持NIDA开发治疗可卡因依赖的有效药物的使命。它还将提供支持或反对上述假设的证据，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。

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.