Medication Development for Cocaine Dependence

描述（由申请人提供）：尽管在过去的二十年里进行了大量的科学研究，但没有一种药物被证明是对可卡因依赖的有效治疗。可卡因的奖赏效应主要通过中脑边缘多巴胺（DA）通路介导。然而，专注于开发抑制中脑DA释放或产生突触后DA受体阻断的药物的实验表明，这些都不是可卡因依赖的有效治疗方法。因此，我们建议测试一种不同的策略来开发一种治疗可卡因依赖的药物：仅仅是中脑DA释放的反对就足够了，还是我们可以通过同时调节DA功能表达来更可靠地控制DA效应？中脑da相关奖励的表达可能是通过抑制γ -氨基丁酸（GABA）来介导的，这种抑制是通过从伏隔核投射到皮层的传出信号来实现的，而这些传入信号本身是在兴奋性氨基酸（EAA）通路的张力控制下进行的。因此，我们有理由假设，一种促进中脑gaba能功能并抑制EAAs作用的药物，除了减少中脑DA释放外，还通过抑制中脑DA功能的表达，更可靠地减少可卡因的奖赏效应。我们最近的概念验证表明，托吡酯（一种减少DA功能表达的果糖吡喃糖衍生物）可以有效地减少酒精依赖个体的渴望和酒精消耗，从而证明了这种新方法的前景。接下来，我们将通过在随机临床试验（RCT）中确定托吡酯是否显著降低与滥用倾向相关的可卡因奖励效应来扩展我们的假设检验。在这项随机对照试验中，男性和女性可卡因依赖者将被随机分配接受托吡酯（最高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，为期12周。

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.