Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and meth ylphenidate have similar in vitro affinities for DAT the abuse of methylphe nidate in humans is substantially lower than of cocaine. To test if differe nces in in vivo potency at the DAT between these two drugs could account fo r the differences in their abuse liability we compared the levels of DAT oc cupancies that we had previously reported separately for intravenous methyl phenidate in controls and for intravenous cocaine in cocaine abusers. DAT o ccupancies were measured with Positron Emission Tomography using [C-11]coca ine, as a DAT ligand, in 8 normal controls for the methylphenidate study an d in 17 active cocaine abusers for the cocaine study. The ratio of the dist ribution volume of [C-11]cocaine in striatum to that in cerebellum, which c orresponds to Bmax/Kd +1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two d rugs. Methylphenidate and cocaine produced comparable dose-dependent blocka de of DAT with an estimated ED50 (dose required to block 50% of the DAT) fo r methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs i nduced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocai ne. The similar in vivo potencies at the DAT for methylphenidate than for c ocaine are in agreement with their reported relative in vitro affinities (K i 390 nM and 640 nM respectively), which is likely to reflect the similar d egree of uptake (8-10% of the injected dose) and regional distribution of t hese two drags in the human brain. Thus, differences in the in vivo potency of these two drugs at the DAT cannot be responsible for the differences in their rate of abuse in humans. Other variables i.e. longer duration of met hylphenidate's side effects may counterbalance its reinforcing effects. (C) 1999 Elsevier Science Inc.