Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain.
Methylphenidate (Ritalin) is the most commonly prescribed psychoactive drug in children for the treatment of attention deficit hyperactivity disorder (ADHD), yet the mechanisms responsible for its therapeutic effects are poorly understood. Whereas methylphenidate blocks the dopamine transporter (main mechanism for removal of extracellular dopamine), it is unclear whether at doses used therapeutically it significantly changes extracellular dopamine (DA) concentration. Here we used positron emission tomography and [(11)C]raclopride (D2 receptor radioligand that competes with endogenous DA for binding to the receptor) to evaluate whether oral methylphenidate changes extracellular DA in the human brain in 11 healthy controls. We showed that oral methylphenidate (average dose 0.8 +/- 0.11 mg/kg) significantly increased extracellular DA in brain, as evidenced by a significant reduction in B(max)/K(d) (measure of D2 receptor availability) in striatum (20 +/- 12%; p < 0.0005). These results provide direct evidence that oral methylphenidate at doses within the therapeutic range significantly increases extracellular DA in human brain. This result coupled with recent findings of increased dopamine transporters in ADHD patients (which is expected to result in reductions in extracellular DA) provides a mechanistic framework for the therapeutic efficacy of methylphenidate. The increase in DA caused by the blockade of dopamine transporters by methylphenidate predominantly reflects an amplification of spontaneously released DA, which in turn is responsive to environmental stimulation. Because DA decreases background firing rates and increases signal-to-noise in target neurons, we postulate that the amplification of weak DA signals in subjects with ADHD by methylphenidate would enhance task-specific signaling, improving attention and decreasing distractibility. Alternatively methylphenidate-induced increases in DA, a neurotransmitter involved with motivation and reward, could enhance the salience of the task facilitating the "interest that it elicits" and thus improving performance.
Volkow
N D
ND
Departments of Medical and Chemistry, Brookhaven National Laboratory, Upton, New York 11973, USA.
Wang
G
G
Fowler
J S
JS
Logan
J
J
Gerasimov
M
M
Maynard
L
L
Ding
Y
Y
Gatley
S J
SJ
Gifford
A
A
Franceschi
D
D
D000284:Administration, Oral; D000328:Adult; D001519:Behavior / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000378:metabolism / Q000493:pharmacokinetics; D065127:Dopamine D2 Receptor Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D005110:Extracellular Space / Q000378:metabolism*; D014644:Genetic Variation; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008774:Methylphenidate / Q000008:administration & dosage* / Q000097:blood; D009419:Nerve Tissue Proteins; D020891:Raclopride / Q000378:metabolism / Q000493:pharmacokinetics; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D014055:Tomography, Emission-Computed
D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017448:Receptors, Dopamine D2; D008774:Methylphenidate; D020891:Raclopride; D004298:Dopamine