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Christine Guilfoy
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Lifting The Curtain On How Ritalin Packs Its 1-2 Punch

Methylphenidate elevates norepinephrine, suppresses nerve signal transmission

BETHESDA, MD. (May 30, 2006) – Methylphenidate (Ritalin) elevates norepinephrine levels in the brains of rats to help focus attention while suppressing nerve signal transmissions in the sensory pathways to make it easier to block out extraneous stimuli, a Philadelphia research team has found.

Their report in the Journal of Neurophysiology helps explain how a stimulant aids people with attention deficit and hyperactivity disorders to improve their focus without increasing their motor activity. Methylphenidate, prescribed under the brand name Ritalin, has been used for more than 20 years, mostly in children, to treat attention deficit hyperactivity disorder (ADHD) and attention deficit disorder (ADD). The drug can also help people who don’t suffer either disorder to attend better to a cognitive task.  

Despite its wide use, little is known about how the drug, a chemical cousin of amphetamines, produces its therapeutic effects. Researchers want to unlock the mystery of why the drug has the paradoxical effect of decreasing hyperactive behavior and increasing the ability to focus, even though it is a stimulant, said Barry Waterhouse, the study’s senior author.

“We’re developing a series of behavioral and electrophysiological assays for examining the actions of drugs like methylphenidate,” Waterhouse said. “If we can show exactly how methylphenidate works, we may be able to produce even more effective drugs and provide a better understanding of the physiology underlying ADHD.”

The study, using rats, is the first to document the increase in norepinephrine and suppression of the neuronal response in this sensory pathway of the brain. “Methylphenidate enhances noradrenergic transmission and suppresses mid- and long-latency sensory responses in the primary somatosensory cortex of awake rats,” by Philadelphia-based researchers Candice Drouin, University of Pennsylvania; Michelle Page, Thomas Jefferson University; and Barry Waterhouse, Drexel University College of Medicine appears online in the Journal of Neurophysiology, published by The American Physiological Society.

From whiskers to brain

The researchers stimulated rats’ whiskers while recording the activity of the neurons in the sensory pathways that convey this sensation from the whiskers to the cerebral cortex. They compared the rat’s sensory pathway response to the whisker stimulation when receiving two different doses of methylphenidate. They found that both the low and moderate doses of methylphenidate:

• Elevated norepinephrine in the area of the brain that processes information related to whisker movement. Norepinephrine helps transmit sensory information from the periphery to the brain.

• Suppressed the long latency phase of the brain’s neuronal response to whisker-related sensory stimuli. Suppression of the sensory neuronal response in this way is believed to help filter extraneous stimuli, Waterhouse explained. With the extraneous stimuli out of the way, the individual is better able to attend to the important stimuli.

In addition, the researchers found that the higher dose caused the rats to increase motor activity, while the lower dose did not.

Scientists still have much to learn about methylphenidate, which has an impact on neural circuits throughout the entire brain, not just the sensory pathway studied in this paper, Waterhouse noted. The changes that occur in this sensory pathway may affect other areas of the brain and changes in other areas of the brain may affect this pathway. In addition to sensory pathways, other scientists are studying how the drug affects cognitive and emotional areas of brain.

Next steps

“This experiment adds to our knowledge of what the drug is doing at the cellular level and gives us a springboard to other studies,” Waterhouse said. “One question now is, how does the individual’s perception of what is an important stimulus factor into the equation?”

Researchers in this area keep in touch and share their results, Waterhouse said. One group, for example, is looking at the drug’s effects on dopamine and norepinephrine in the prefrontal cortex, he noted. These results will eventually have to be combined, as changes in one area of the brain are likely to affect other areas.

“We’ve been thinking about this for a long time,” Waterhouse said of his research. “We hope to have a good idea of the drug’s action when we put it all together.”

One broad question that intrigues researchers is whether ADHD traces back to the same area of the brain as attention deficit disorder, a similar condition but one in which hyperactivity isn’t a symptom.

They also want to know whether Ritalin has any toxic or long-lasting effects, not only for ADHD patients, but also for individuals taking the drug who do not suffer from ADHD or ADD. Methylphenidate use is on the rise among college students who solicit prescriptions from friends or siblings diagnosed with ADHD and use the drug to postpone fatigue and stay alert and focused while studying for exams or completing projects, Waterhouse said.

Source and funding

“Methylphenidate enhances noradrenergic transmission and suppresses mid- and long-latency sensory responses in the primary somatosensory cortex of awake rats,” by Candice Drouin, Laboratory of Neuromodulation and Behavior, Dept. of Psychiatry, University of Pennsylvania; Michelle Page, Depart. of Neurosurgery, Thomas Jefferson University; and Barry Waterhouse, Dept. of Neurobiology and Anatomy, Drexel University College of Medicine. The study appears in the May issue of the Journal of Neurophysiology published by The American Physiological Society.

Research was supported by a grant from the National Institute of Mental Health (Waterhouse).

Editor’s note: The media may obtain a copy of Drouin et al. by contacting Christine Guilfoy, American Physiological Society, (301) 634-7253, (978) 290-2400 (cell), or cguilfoy@the-aps.org.

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The American Physiological Society was founded in 1887 to foster basic and applied bioscience. The Bethesda, Maryland-based society has 10,500 members and publishes 14 peer-reviewed journals containing almost 4,000 articles annually.

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APS  provides a wide range of research, educational and career support and programming to further the contributions of physiology to understanding the mechanisms of diseased and healthy states. In 2004, APS received the Presidential Award for Excellence in Science, Mathematics and Engineering Mentoring (PAESMEM).

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