Methylphenidate (MPH) is the most commonly prescribed drug for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). We have used Positron Emission Tomography (PET) to investigate the mechanism of action of MPH in the human brain. We have shown (a) that oral MPH reaches peak concentration in the brain 60–90 minutes after its administration, (b) that therapeutic doses of MPH block more than 50% of the dopamine transporters (DAT), and (c) that of the two enantiomers that compose MPH, it is d-threo-methylphenidate (d-MPH) and not l-threo-methylphenidate (l-MPH) that binds to the DAT. We have also shown that therapeutic doses of MPH significantly enhance extracellular dopamine (DA) in the basal ganglia, which is an effect that appears to be modulated by the rate of DA release and that is affected by age (older subjects show less effect). Thus, we postulate (a) that MPH's therapeutic effects are in part due to amplification of DA signals, (b) that variability in responses is in part due to differences in DA tone between subjects, and (c) that MPH's effects are context dependent. Because DA enhances task specific neuronal signaling and decreases noise, we also postulate that MPH-induced increases In DA could improve attention and decrease distractibility; and that since DA modulates motivation, the increases in DA would also enhance the saliency of the task facilitating the “interest it elicits” and thus improving performance.

1. Rat liver mitochondria make hippurate at up to 4 nmol/min per mg of protein. The rate of synthesis supported by oxidation of glutamate with exogenous Pi present is identical with that supported by ATP plus oligomycin. Lower rates were obtained with other respiratory substrates, and when glutamate was used without Pi. 2. A matrix localization for hippurate synthesis is indicated by the latency of benzoyl-CoA synthetase and glycine N-acyltransferase to their extramitochondrial substrates, failure of exogenous benzoyl-CoA to inhibit incorporation of [14C]hippurate and inhibition of hippurate synthesis supported by ATP, but not glutamate, by carboxyatractyloside. 3. The relative activities of the individual enzymes and the mitochondrial content of benzoyl-CoA in the presence and absence of glycine suggest that hippurate synthesis is rate-limited by formation of benzoyl-CoA. 4. The increases in rates of ATP hydrolysis and of O2 consumption on the addition of benzoate and glycine were in good agreement with those required to support hippurate synthesis. The increase in respiration indicates that State-4 respiration [Chance & Williams (1957) Adv. Enzymol 17, 65-134] is not used, with these conditions, for ATP synthesis.

Several recent neuroimaging studies in humans and in monkeys using different radiotracers have reported widely differing values of dopamine transporter (DAT) occupancy by doses of cocaine which are perceived as reinforcing by humans. Here we tested the hypothesis that the measurement of DAT occupancies by drugs with fast pharmacokinetics such as cocaine requires a radioligand with similar kinetics in order to effectively compete with the drug. We measured DAT occupancy by four different doses of cocaine (1.0, 0.5, 0.25, and 0.1 mg/kg) using [11C]d-threo-methylphenidate (a radiotracer which binds rapidly to the DAT in vivo) and compared them to estimates reported previously using [11C]cocaine in the same two baboons and with the same four doses of cocaine [Volkow et al. (1996b) Synapse 24:399-402). Cocaine reduced [11C]d-threo-methylphenidate binding in striatum in a dose-dependent manner, and values were significantly correlated with those obtained previously with [11C]cocaine (r = 0.9, F = 37, P < 0.001). The ED50s (50% occupancy of DAT by cocaine) were 0.27 and 0.17 mg/kg for [11C]d-threo-methylphenidate and [11C]cocaine, respectively. This is significantly lower than values obtained with labeled beta-CIT and other similar radiotracers with a slow uptake and clearance (ED50s: 3-7 mg/kg). We conclude that in vivo measurements of DAT occupancy by rapidly clearing drugs like cocaine requires the use of radiotracers having similar kinetics to the drug itself.