COMBINATION PHARMACOTHERAPIES FOR COCAINE ADDICTION

可卡因成瘾的联合药物治疗

• 批准号: 6206910
• 负责人: KIMBERLY P LINDSEY
• 金额: $ 3.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6206910
• 关键词: Macaca mulatta; cocaine; combination chemotherapy; dopamine antagonists; drug abuse; drug abuse chemotherapy; nonhuman therapy evaluation; positron emission tomography; psychopharmacology; serotonin inhibitor; substance abuse related behavior

Development of an effective medication for human cocaine addicts requires a better understanding of the mechanism of cocaine reinforced behavior. Cocaine is a nonspecific monoamine reuptake blocker. Cocaine's reinforcing properties are thought to arise primarily from its blockade of the dopamine transporter (DAT) although it acts equipotently to inhibit uptake of serotonin. A growing number of studies support the hypothesis that interactions between dopaminergic and serotonergic systems may be important in mediating and/or modulating the reinforcing properties of cocaine. The proposed experiments will assess three DAT inhibitors, a mixed action dopamine/serotonin uptake inhibitor, and the combination of a DAT inhibitor coadministered with an SSRI for their ability to decrease cocaine reinforced responding in rhesus monkeys. Additionally, neuroimaging using positron emission tomography (PET) will be used to quantify the proportional degree of DAT occupancy associated with this effect for each drug. Combining DAT inhibition with serotonin transporter inhibition may be more effective than either type of therapy alone, and may exert significant behavioral effects at lower doses than a DAT selective ligand alone.

为人类可卡因成瘾者开发有效的药物需要更好地了解可卡因强化行为的机制。 辅酶A是一种非特异性单胺再摄取阻滞剂。 可卡因的强化特性被认为主要来自于其对多巴胺转运蛋白（DAT）的阻断，尽管它的作用等同于抑制5-羟色胺的摄取。 越来越多的研究支持这一假设，即多巴胺能和多巴胺能系统之间的相互作用可能是重要的介导和/或调节可卡因的增强性能。 拟议的实验将评估三种DAT抑制剂，一种混合作用的多巴胺/5-羟色胺摄取抑制剂，以及DAT抑制剂与SSRI联合给药降低恒河猴可卡因强化反应的能力。 此外，使用正电子发射断层扫描（PET）的神经成像将用于量化与每种药物的这种效应相关的DAT占用比例程度。 将DAT抑制与5-羟色胺转运体抑制组合可能比单独的任一类型的治疗更有效，并且可以在比单独的DAT选择性配体更低的剂量下发挥显著的行为效应。