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 poor ly understood. Whereas methylphenidate blocks the dopamine transporter (mai n mechanism for removal of extracellular dopamine), it is unclear whether a t doses used therapeutically it significantly changes extracellular dopamin e (DA) concentration. Here we used positron emission tomography and [C-11] raclopride (D2 receptor radioligand that competes with endogenous DA for bi nding to the receptor) to evaluate whether oral methylphenidate changes ext racellular DA in the human brain in 11 healthy controls. We showed that ora l methylphenidate (average dose 0.8 +/- 0.11 mg/kg) significantly increased extracellular DA in brain, as evidenced by a significant reduction in B-ma x/K-d (measure of D2 receptor availability) in striatum (20 +/- 12%; p < 0. 0005). These results provide direct evidence that oral methylphenidate at d oses within the therapeutic range significantly increases extracellular DA in human brain. This result coupled with recent findings of increased dopam ine transporters in ADHD patients (which is expected to result in reduction s 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 amplific ation of spontaneously released DA, which in turn is responsive to environm ental stimulation. Because DA decreases background firing rates and increas es signal-to-noise in target neurons, we postulate that the amplification o f weak DA signals in subjects with ADHD by methylphenidate would enhance ta sk-specific signaling, improving attention and decreasing distractibility. Alternatively methylphenidate-induced increases in DA, a neurotransmitter i nvolved with motivation and reward, could enhance the salience of the task facilitating the "interest that it elicits" and thus improving performance.