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.
