Serum and brain concentrations of methylphenidate: implications for use and abuse.

When used to treat children with Attention Deficit Hyperactivity Disorder, methylphenidate (MPH) acts primarily by blocking the dopamine (DA) transporter (DAT) and increasing extracellular DA in the striatum. This is strikingly similar to the mechanism of action of cocaine, a primary stimulant drug of abuse. When administered intravenously, MPH like cocaine has reinforcing effects (euphoria) at doses that exceed a DAT blockade threshold of 60%. When administered orally at clinical doses, the pharmacological effects of MPH also exceed this threshold, but reinforcing effects rarely occur. Here we discuss the pharmacokinetic properties of MPH in serum (and in brain) that differ for oral and intravenous routes of administration and the importance of acute tolerance in determining pharmacodynamic effects in clinical use and illegal abuse. We suggest that intravenous administration of MPH mimics the rapid phasic cell firing of DA neurons, which may be a critical factor associated with reinforcing effects and abuse, while oral administration of MPH mimics the tonic DA cell firing, which may be a critical factor associated with clinical effects.