COMBINATION PHARMACOTHERAPIES FOR COCAINE ADDICTION

开发一种治疗人类可卡因成瘾者的有效药物需要更好地理解可卡因强化行为的机制。可卡因是一种非特异性单胺再摄取阻滞剂。可卡因的增强作用被认为主要是因为它阻断了多巴胺转运体(DAT)，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样的假设，即多巴胺能和5-羟色胺能系统之间的相互作用在调节和/或调节可卡因的增强特性方面可能是重要的。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，以及一种DAT抑制剂与SSRI联合使用的能力，以减少恒河猴对可卡因增强的反应。此外，使用正电子发射断层扫描(PET)的神经成像将被用来量化每种药物与这种效果相关的DAT占有率的比例程度。联合使用DAT抑制和5-羟色胺转运体抑制可能比单独使用任何一种治疗方法更有效，并且在较低剂量下可能比单独使用DAT选择性配体产生显著的行为效应。

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.