Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of "high"

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Using positron emission tomography (PET), we previously showed that intravenous cocaine induced a significant level of DAT blockade, which was associated with the intensity for self-reports of "high" in cocaine abusers. In this study, we measured D AT occupancies after intravenous methylphenidate and assessed whether they also were associated with the "high". Occupation of DAT by intravenous MP w as measured with PET using [C-11]cocaine; as a DAT ligand, in eight normal control subjects tested with different methylphenidate doses. The ratio of the distribution volume of [C-11]cocaine in striatum to that in cerebellum, which corresponds to B-max/Kd+1, was used as measure of DAT availability. In parallel, self-reports of "high" were measured. Methylphenidate produced a dose-dependent blockade of DAT with an estimated ED50 of 0.075 mg/kg. DA T occupancies were significantly correlated with the "high" (p <.03). Howev er, four of the eight subjects, despite having significant levels of DAT bl ockade, did not perceive the "high". Methylphenidate is as effective as coc aine in blocking DAT in the human brain (cocaine ED50 = 0.13 mg/kg), and DA T blockade, as for cocaine, was also associated with the "high". However, t he fact that there were subjects who despite significant DAT blockade did n ot experience the "high" suggests that DAT blockade, although necessary, is not sufficient to produce the "high".