Ritalin May Cause Long-Lasting Changes In Brain-Cell Function, University At Buffalo Researchers Find

SAN DIEGO -- Scientists at the University at Buffalo have shown that the drug methylphenidate, the generic form of Ritalin, which physicians have considered to have only short-term effects, appears to initiate changes in brain function that remain after the therapeutic effects have dissipated.

The changes appear to be similar to those that occur with other stimulant drugs such as amphetamine and cocaine, said Joan Baizer, Ph.D., UB professor of physiology and biophysics and senior author of the study. Results of the research were presented here today (Nov. 11, 2001) at the annual meeting of the Society for Neuroscience.

"Clinicians consider Ritalin to be short-acting," said Baizer. "When the active dose has worked its way through the system, they consider it 'all gone.' Our research with gene expression in an animal model suggests that it has the potential for causing long-lasting changes in brain cell structure and function." Ritalin is the drug of choice for the treatment of attention deficit disorder in children.

Baizer stated, however, that while the neuronal changes are similar to those seen with cocaine and other psychoactive drugs, it does not seem that methylphenidate in very low doses, as used therapeutically, produces much potential for drug abuse.

"Children have been given Ritalin daily for many years, and it is extremely effective and beneficial, but it's not quite as simple as a short-acting drug," Baizer said. "We need to look at it more closely." Baizer added: "Ritalin does appear to be safe when used properly, but it is still important to ask what it is doing in the brain."

Previous work in other laboratories has shown that high doses of amphetamine and cocaine switch on certain genes called "immediate early genes" in particular brain cells and that this action causes changes in some aspects of nerve cell function. One of those genes is called "c-fos." Amphetamine and cocaine both cause c-fos activity in the striatum, a brain structure important for both movement and motivation, and the presence of c-fos activity there has been implicated in the mechanism of addiction, Baizer said. The researchers wanted to see if methylphenidate caused c-fos activation in the same parts of the brain, and at the same levels, as the other drugs.

Using young rats as an animal model, they gave one group sweetened milk containing a relatively high dose of methylphenidate (20 mg/kg). Considering the differences in metabolism between rats and humans, this is comparable approximately to a dose on the high end of the range that is used therapeutically, Baizer said. They administered the drug at a time during the rat's 24-hour cycle that would simulate the timing of a child's dose. Another group received just sweetened milk. After 90 minutes, the optimal time for c-fos development in brain cells, the brains of both groups were analyzed for the presence of c-fos.

Results showed there were many more neurons with c-fos activity in the brains of rats given methylphenidate, particularly in the striatum, Baizer said, than in the brains of control rats. Rats receiving no treatment and sacrificed after a period of rest showed still less c-fos activity, suggesting that some of the c-fos activity is related to moving around in the home cage and not a pure drug effect.

"These data do suggest that there are effects of Ritalin on cell function that outlast the short term and we should sort that out," Baizer said. "There is no indication of tolerance, but we have no idea if there is adaptation to the effects."

One next step, she said, is to use microarray technology to see what other genes are turned on in response to short and long-term Ritalin use. Additional researchers on the study were Ashley Acheson, a graduate student in the UB Department of Psychology; Alexis Thompson, Ph.D., a research scientist at the UB Research Institute on Addictions, and Mark B. Kristal, Ph.D., UB professor of psychology.

        ``This is an important stepping stone but there is a long road to travel,'' Hyman said.

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