Relationship between blockade of dopamine transporters by oral methylphenidate and the increases in extracellular dopamine: therapeutic implications

Synapse. 2002 Mar 1;43(3):181-7. doi: 10.1002/syn.10038.


Methylphenidate (Ritalin) is an effective drug in the treatment of attention deficit hyperactivity disorder. However, the doses required therapeutically vary significantly between subjects and it is not understood what determines these differences. Since methylphenidate's therapeutic effects are in part due to increases in extracellular DA secondary to blockade of dopamine transporters (DAT), the variability could reflect differences in levels of DAT blockade. Here we used PET to assess if for a given dose of methylphenidate the differences in DAT blockade account for the variability in methylphenidate-induced increases in extracellular DA. Ten healthy adult subjects were tested before and 60 min after oral methylphenidate (60 mg) with PET to estimate DAT occupancy (with [(11)C]cocaine as the radioligand) and levels of extracellular DA (with [(11)C]raclopride as the D2 receptor radioligand that competes with endogenous DA for binding to the receptor). Methylphenidate significantly blocked DAT (60 +/- 11%) and increased extracellular DA in brain (16 +/- 8% reduction in [(11)C]raclopride binding in striatum). However, the correlation between methylphenidate-induced DAT blockade and DA increases was not significant. These results indicate that for a given dose of methylphenidate, individual differences in DAT blockade are not the main source for the intersubject variability in MP-induced increases in DA. This finding suggests that individual differences in response to MP are due in part to individual differences in DA release, so that for an equivalent level of DAT blockade, MP would induce smaller DA changes in subjects with low than with high DA cell activity.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Oral
  • Adult
  • Age Factors
  • Attention Deficit Disorder with Hyperactivity / drug therapy
  • Attention Deficit Disorder with Hyperactivity / metabolism
  • Attention Deficit Disorder with Hyperactivity / physiopathology
  • Behavior / drug effects
  • Behavior / physiology
  • Brain / diagnostic imaging
  • Brain / drug effects*
  • Carbon Radioisotopes / metabolism
  • Cardiovascular Physiological Phenomena / drug effects
  • Cocaine / metabolism
  • Dopamine / metabolism*
  • Dopamine Antagonists / metabolism
  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors / pharmacology*
  • Extracellular Space / drug effects*
  • Extracellular Space / metabolism
  • Humans
  • Male
  • Membrane Glycoproteins*
  • Membrane Transport Modulators*
  • Membrane Transport Proteins / antagonists & inhibitors*
  • Membrane Transport Proteins / metabolism
  • Methylphenidate / blood
  • Methylphenidate / pharmacology*
  • Neostriatum / diagnostic imaging
  • Neostriatum / drug effects
  • Nerve Tissue Proteins*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Raclopride / metabolism*
  • Tomography, Emission-Computed
  • Up-Regulation / drug effects*
  • Up-Regulation / physiology


  • Carbon Radioisotopes
  • Dopamine Antagonists
  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • Membrane Glycoproteins
  • Membrane Transport Modulators
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • SLC6A3 protein, human
  • Methylphenidate
  • Raclopride
  • Cocaine
  • Dopamine