Early Exposure to Ritalin May Blunt Desire for Cocaine Later in Life

December 2, 2001 -- Belmont, MA -- Exposure to Ritalin early in life may make one less vulnerable to the allure of cocaine later, according to a new report by McLean researchers. Susan Andersen, PhD, William Carlezon, PhD, and their colleagues found adult rats that were given Ritalin as juveniles spent less time seeking out cocaine than did their Ritalin-free peers. Moreover, in some cases, the rats appeared to actively avoid places where they had been exposed to cocaine in the past.

The findings, which appear in the Dec. 3 online version of Nature Neuroscience, could help resolve several controversies surrounding the use of Ritalin, or methylphenidate, a stimulant prescribed for children who have an abnormally high level of activity or attention deficit hyperactivity disorder (ADHD).

While Ritalin appears to calm hyperactive children and to help focus those with ADHD, some worry that it may lead to the abuse of other drugs later in life. The discovery that Ritalin-reared rats find cocaine less rewarding, or more aversive, appears to contradict this idea, at least in the case of cocaine.

Another concern surrounding Ritalin is that it may cause permanent changes in the brain. Andersen and her colleagues found that the Ritalin-exposed animals did, in fact, display lasting neurological changes. Most notably, they had elevated levels of a protein called CREB, which plays a role in a wide variety of brain functions.

Is Ritalin working its cocaine-aversive effects by upping CREB production? The researchers think this may be the case, at least in part. Several years ago, Carlezon and his colleagues showed that rats whose CREB levels had been increased artificially (not by Ritalin) were much less responsive to cocaine. While cocaine-avoidance behavior might be beneficial, high levels of CREB could also have harmful consequences. The changes in CREB occur in a part of the brain that is involved in a variety of other basic activities, such as eating and sex.

If Ritalin works by tinkering with CREB levels, it could produce a mixed bag of effects. "Some of these changes may be potentially good," said Andersen of McLean Hospital’s Developmental

Psychopharmacology Laboratory. "Some of them may not be very good. CREB makes drugs of abuse less rewarding but does it make other natural rewards, such as eating and sex, less pleasurable?"

"It looks like Ritalin might change the brain forever," said Carlezon, director of McLean Hospital’s Behavioral Genetics Laboratory. "We have to be ready to deal with the consequences of that."

Inspired by the twin horns of the Ritalin dilemma—that it might lead to brain changes and drug abuse later—and also by a 1999 report suggesting that children taking Ritalin used other drugs less frequently, the researchers set out to study the effects of Ritalin in rats. They raised two sets of rats. One was given two injections of Ritalin a day for 15 days, during the rat equivalent of preadolescence. The other group was given saline. The rats were left alone for 25 days. At 60 days, the rat equivalent of adulthood, they were tested.

Each set of rats—saline- and Ritalin-exposed—was divided into three groups, each of which was exposed to cocaine in a special compartment. The first set was injected with a low dose (5mg/kg) of cocaine, the second with a moderate dose (10mg/kg), and the third with a high drug dose (20mg/kg). The researchers then measured how much time the rats spent in the special drug-associated compartment as compared to a second, non-drug associated compartment.

Low-dose rats, whether saline- or Ritalin-reared, exhibited no preference for either compartment. But there were striking differences between the other groups. Whereas the moderate- and high-dose controls spent more and more time in the cocaine-associated compartment, the Ritalin-reared animals were much less enthusiastic. Those exposed to a moderate dose of the drug actively avoided the compartment. Those exposed to high levels of cocaine spent somewhat more time in the cocaine-associated compartment, though not enough to be significant. "Their response was definitely blunted," said Andersen.

She and her colleagues repeated the experiments, this time with rats that were first given Ritalin during adulthood, rather than preadolescence. While the rats displayed an indifferent response to cocaine, they never got to the point of avoiding it altogether. The disparity between the adult- and juvenile-Ritalin-exposed rats suggests that the drug has different long-term effects in the brains of children and adults.

"We don’t yet know enough about what drugs do to a developing brain," Andersen said. "But what this study shows is that a child's brain is clearly not wired the same way as an adult brain."