"Methylphenidate [Ritalin] is very effective for the treatment of ADHD," said Brookhaven psychiatrist Nora Volkow, lead author on the study, "but the doses required to achieve clinical responses vary significantly from patient to patient. This new study suggests that this variation may be due, in part, to individual variation in the release of dopamine, a neurotransmitter associated with feelings of reward and pleasure."
Volkow's group at Brookhaven had previously shown that Ritalin exerts its attention-increasing effects by increasing the amount of dopamine in brain cell synapses, the space between cells (see: http://www.bnl.gov/bnlweb/pubaf/pr/2001/bnlpr011501a.html). It does this by blocking dopamine transporters, proteins that normally transport dopamine from the synapse back into dopamine cells, recycling it for future use. More dopamine in the synapse yields a stronger reward signal, and more enjoyment of and motivation to perform certain tasks.
Volkow hypothesized that variation in response to Ritalin might be due to differences in the drug's ability to block the transporters in individual patients. To test this hypothesis, the Brookhaven scientists used a technique called positron emission tomography (PET) to measure dopamine transporter blockage and extracellular dopamine in ten healthy adult volunteers before and 60 minutes after being given a standard dose of Ritalin (60 milligrams). Transporter blockage and dopamine levels were measured on different days.
Transporter blockage was measured by injecting each volunteer with a radioactive label that binds to available, or free, dopamine transporters. The strength of the radioactive signal picked up by the PET camera indicates how many transporters are blocked by Ritalin (the lower the binding of the radiotracer, the higher the blockage by Ritalin).
Dopamine levels were measured by injecting volunteers with a different radioactive label, one that competes with dopamine in the brain for binding to receptors. In this case, the lower the signal from the radioactive label, the higher the level of dopamine in the synapse.
The findings: The fixed dose of Ritalin significantly blocked dopamine transporters and significantly increased extracellular dopamine, as expected. However, while the magnitude of the blockade of the dopamine transporters by Ritalin was similar across subjects, the magnitude of the increases in dopamine differed markedly between subjects. As a result, the correlation between Ritalin-induced dopamine transporter blockade and the increase in dopamine levels was not significant. In fact, there were subjects in whom Ritalin blocked significant numbers of dopamine transporters, but did not increase extracellular dopamine. So the level of transporter blockade could not explain the variability in Ritalin-induced changes in dopamine.
"We interpret this lack of a correlation as an indication that the dopamine increases were due not just to dopamine transporter blockade by Ritalin but to individual variability in the amount of dopamine released by the dopamine cells," Volkow said. "This means that, for an equivalent level of transporter blockage, Ritalin will induce smaller dopamine changes in a patient with low dopamine cell activity than in one with high dopamine cell activity."
"This may explain why some patients do not respond to Ritalin," Volkow said. Even if the drug effectively blocks dopamine transporters, it may not significantly increase extracellular dopamine if dopamine production is low. This study, one more step in understanding how Ritalin works, may help doctors find other ways to treat patients who do not respond to the drug.
This work was funded by the U.S. Department of Energy, which supports basic research in a variety of scientific fields, and the National Institute on Drug Abuse, a division of the National Institutes of Health.
For the web version of this press release, go to: http://www.bnl.gov/bnlweb/pubaf/pr/2002/bnlpr030102.htm
The U.S. Department of Energy's Brookhaven National Laboratory (http://www.bnl.gov) conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies. Brookhaven also builds and operates major facilities available to university, industrial, and government scientists. The Laboratory is managed by Brookhaven Science Associates, a limited liability company founded by Stony Brook University and Battelle, a nonprofit applied science and technology organization.
Note to local editors: Nora Volkow lives in Shoreham, New York.
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Synapse