Results of the research will be presented Sunday 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 Ôall 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.
She 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 Department of Psychology; Alexis Thompson, a research
scientist at the Research Institute on Addictions, and Mark B. Kristal,
professor of psychology.
