Adaptive Clinical Trial of Adenosine A2a Antagonist in Cocaine Dependence

长期使用可卡因可能会破坏单胺系统（包括多巴胺）。这又可 在重要的认知和行为过程中造成可测量的功能障碍。药物治疗 与增强多巴胺（DA）功能的兴奋剂一起使用， 和改善行为功能-支持这些过程是相关的概念。在 开发可卡因依赖的新药物疗法，重要的一步是充分了解 可卡因依赖的潜在药物的精神药理学特性，包括 主观、生理、辨别和行为影响。 选择性腺苷（A2 A）受体拮抗剂可能在DA的调节中起关键作用 通过间接增强DA受体的激活来实现神经传递。此外，A2 A拮抗剂抑制 大麻素CBI受体激活，表明减少并发大麻的潜在机制 在可卡因依赖患者中使用。A2 A拮抗剂可能对并发大麻提供额外益处 在可卡因依赖者中使用可卡因，因为可卡因-大麻双重使用者提出了独特的治疗挑战。 本项目旨在评价新型A2 A拮抗剂SYN 115。其类似兴奋剂的作用可能有助于 与（a）DA耗竭和（B）DA-CB 1相互作用相关的情感和行为缺陷。因此，委员会认为， 该项目的目的是描述SYN 115在可卡因患者中的精神药理学特征 依赖、可卡因依赖伴大麻使用和对照。采用急性和 慢性给药设计，将使用完善的精神药理学进行三个实验 方法，以表征剂量-反应关系。将采用混合模式战略，以（a） 利用受试者内重复测量设计的能力，以及（B）比较可卡因依赖性和 健康的对照组。措施将包括药物歧视，主观影响， 心血管效应、行为抑制（冲动）、工作记忆、逆转学习和决策 制作。这些数据将补充和提供有价值的信息，我们的平行临床试验， 这些药物治疗可卡因依赖

Chronic cocaine use may produce disruption of monoamine systems (including dopamine). This may in turn contribute to measurable dysfunction in important cognitive and behavioral processes. Pharmacotherapy with stimulants that enhance dopamine (DA) function has shown efficacy in treating cocaine dependence and improving behavioral function ~ supporting the notion that these processes are related. In the development of novel pharmacotherapies for cocaine dependence, an important step is a full understanding of the.psychopharmacological properties of potential medications for cocaine dependence, including subjective, physiological, discriminative and behavioral effects. Selective adenosine (A2A) receptor antagonists may play a key role in the modulation of DA neurotransmission by indirectly enhancing DA receptor activation. Additionally, A2A antagonists inhibit cannabinoid CBI receptor activation, suggesting a potential mechanism for reducing concurrent marijuana use in cocaine dependent patients. A2A antagonists may provide additional benefit on concurrent marijuana use in cocaine dependence, as dual cocaine-marijuana users present unique treatment challenges. This project proposes to evaluate the novel A2A antagonist SYN 115. Its stimulant-like effects may help with affective and behavioral deficiencies related to (a) DA depletion and (b) DA-CB1 interactions. Accordingly, the project aims to characterize the psychopharmacology of SYN115 in individuals with cocaine dependence, cocaine dependence with concurrent marijuana use, and controls. Employing both acute and chronic dosing designs, three experiments will be conducted using well-established psychopharmacological methods in order to characterize dose-response relationships. A mixed-model strategy will be utilized to (a) leverage the power of within-subject, repeated measures designs, and (b) compare cocaine dependent and healthy matched-control subjects. Measures will include drug discrimination, subjective effects, cardiovascular effects, behavioral inhibition (impulsivity), working memory, reversal learning, and decision making. These data will compliment and provide valuable information to our parallel clinical trials using these agents to treat cocaine dependence