COMBINATION PHARMACOTHERAPIES FOR COCAINE ADDICTION

开发一种对人类可卡因成瘾者有效的药物需要更好地了解可卡因增强行为的机制。可卡因是一种非特异性单胺再摄取阻滞剂。可卡因的强化特性被认为主要来自于它对多巴胺转运体（DAT）的阻断，尽管它同样抑制血清素的摄取。越来越多的研究支持这样一种假设，即多巴胺能和血清素能系统之间的相互作用在介导和/或调节可卡因的强化特性方面可能很重要。拟议的实验将评估三种DAT抑制剂，一种混合作用多巴胺/血清素摄取抑制剂，以及一种DAT抑制剂与SSRI联合使用，以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作用相关的DAT占用的比例程度。将DAT抑制与5 -羟色胺转运体抑制相结合可能比单独治疗更有效，并且在较低剂量下可能比单独使用DAT选择性配体产生显着的行为效果。

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.