Adaptive Clinical Trial of Adenosine A2a Antagonist in Cocaine Dependence

长期使用可卡因可能会扰乱单胺系统(包括多巴胺)。这可能会反过来 在重要的认知和行为过程中导致可测量的功能障碍。药物治疗 增强多巴胺(DA)功能的兴奋剂在治疗可卡因依赖方面显示出有效性 并改善行为功能-支持这些过程是相关的这一概念。在 开发治疗可卡因依赖的新药物疗法，重要的一步是充分认识 治疗可卡因依赖的潜在药物的精神药理学特性，包括 主观的、生理的、歧视的和行为的影响。 选择性腺苷(A2a)受体拮抗剂可能在多巴胺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，A2a拮抗剂抑制 大麻素CBI受体激活，提示减少并发大麻的潜在机制 在可卡因依赖患者中使用。A2a拮抗剂可能对并发大麻提供额外的好处 在可卡因依赖中使用，因为双重吸食可卡因和大麻的人面临独特的治疗挑战。 本项目建议对新型A2A拮抗剂SYN 115进行评估。其类似兴奋剂的作用可能有助于 情感和行为缺陷与(A)DA耗竭和(B)DA-CB1相互作用有关。因此， 该项目旨在描述SYN115在可卡因个体中的精神药理学特征 依赖、可卡因依赖和同时使用大麻，以及对照。同时使用急性和 慢性给药设计，将使用公认的精神药理学进行三个实验 方法为了描述剂量-反应关系。混合模式战略将用于(A) 利用受试者内部重复测量设计的力量，以及(B)比较可卡因依赖和 健康配对对照组受试者。措施将包括毒品歧视、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。这些数据将补充并为我们的平行临床试验提供有价值的信息 这些药物用于治疗可卡因依赖

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