RATE OF BINDING OF VARIOUS INHIBITORS AT THE DOPAMINE TRANSPORTER IN-VIVO

The rate of entry of drugs into brain is thought to be a factor in the ir abuse liability In this investigation, we have examined the rate of entry and binding at dopamine transporters in mouse striatum for a va riety of dopamine transporter inhibitors. The method utilized was base d on measuring the displacement of H-3-WIN 35,428 from striatal dopami ne transporter sites in vivo at different times. Eleven cocaine analog s (RTI-31, RTI-32, RTI-51, RTI-55, RTI-113, RTI-114, RTI-117, RTI-120, RTI-121, WIN 35,065-2, and WIN 35,428) as well as other dopamine upta ke site blockers (bupropion, nomifensine, and methylphenidate) were co mpared with (-)cocaine for their rates of displacement of H-3-WIN 35,4 28 binding in vivo. The drugs that displayed the fastest occupancy rat es were bupropion, (-) cocaine, nomifensine, and methylphenidate. RTI- 51, RTI-121, RTI-114, RTI-117, RTI-120, RTI-32, RTI-55, and RTI-113, s howed intermediate rates, whereas RTI-31, WIN 35,065-2, and WIN 35,428 exhibited the slowest rates of displacement. While many of the cocain e analogs have proven to be behaviorally and pharmacologically more po tent than (-) cocaine, their rates of entry and binding site occupancy were slower than that for (-) cocaine. Earliest times of transporter occupancy by the different drugs were correlated (although weakly) wit h their degree of lipophilicity (r = 0.59; P < 0.02). Kinetic effects and metabolism of the compounds could complicate the interpretations o f these data. There was no obvious correlation between rate of occupan cy in this animal model and abuse liability in humans, which is consis tent with the notion that other factors are critical as well.