Ritalin May Alter Chemistry of Young Brains

NEW YORK, July 20 -- Children who take methylphenidate (Ritalin) throughout childhood may undergo behavior-modifying brain changes that carry into adulthood, or so investigators found in rats.

Normal rats exposed to methylphenidate during the early stage of brain development exhibited changes in brain regions linked to attention deficit hyperactivity disorder, including areas involved in higher executive function, addiction and appetite, social relationships, and stress, reported Teresa A. Milner, M.D., of Weill-Cornell Medical College here, and colleagues.

The findings suggest that methylphenidate, widely prescribed in the United States for treatment of ADHD, may have significant but largely reversible effects on developing brains, the authors reported in the July 4 issue of the Journal of Neuroscience.

"One thing to remember is that these young animals had normal, healthy brains," said Dr. Milner "In ADHD-affected brains, where the neurochemistry is already somewhat awry, or the brain might be developing too fast, these changes might help 'reset' that balance in a healthy way. On the other hand, in brains without ADHD, Ritalin might have a more negative effect. We just don't know yet."

The alterations included neurochemical and cellular changes -- but not structural changes -- in ADHD-related regions, including the medial prefrontal cortex, striatum, hippocampus, and hypothalamus

But the authors also saw that the changes appeared to be reversible, with alterations in norepinephrine and other catecholamines largely reversed three months after the animals were taken off the drug.

"That's encouraging, and supports the notion that this drug therapy may be best used over a relatively short period of time, to be replaced or supplemented with behavioral therapy," Dr. Milner said. "We're concerned about longer-term use. It's unclear from this study whether Ritalin might leave more lasting changes, especially if treatment were to continue for years. In that case, it is possible that chronic use of the drug would alter brain chemistry and behavior well into adulthood."

The authors injected methylphenidate at 5 mg/kg or vehicle (as placebo) into male rates beginning on their seventh day of life and continuing through day 35. The animals were sacrificed either at day 35 or in adulthood at day 135, and brain sections from littermates were labeled for neurotransmitters and cytological markers with immunocytochemistry.

The investigators looked at 16 specific regions implicated either in the ADHD etiology, methylphenidate effects, or both,

They found that among the rats killed at day 35, the medial prefrontal cortex of those animals given methylphenidate showed 55% greater immunoreactivity for tyrosine hydroxylase, a marker for catecholamines, compared with controls. They also saw in this region 60% more Nissl-stained cells, indicating neuronal growth, and 40% lower norepinephrine transporter immunoreactivity density compared with controls.

In addition, rats given the active drug had a 51% decrease in norepinephrine transporter immunoreactivity in the dentate gyrus of the hippocampus and a 61% expanded distribution of polysialylated form of neural cell adhesion molecule, a marker for new cell generation.

Other changes seen in methylphenidate-treated rats included a decrease of 21% in tyrosine hydroxylase immunoreactivity in the medial striatum, and 10% in neuropeptide Y immunoreactivity in the hypothalamus.

The changes seen at the cellular level were reflected in both weight gain and an increase in anxiety on behavioral testing in the methylphenidate-treated animals, the authors noted.

But after another 100 days had passed, adult rats had decreased anxiety in an elevated plus-maze test, and had a trend toward a decrease in catecholamine marker immunoreactivity in the medial prefrontal cortex.

There were no structural brain changes observed among the methylphenidate -treated rats at either 35 or 135 days, however.

"These findings suggest that developmental exposure to high therapeutic doses of methylphenidate has short-term effects on select neurotransmitters in brain regions involved in motivated behaviors, cognition, appetite, and stress," the investigators wrote. "Although the observed neuroanatomical changes largely resolve with time, chronic modulation of young brains with methylphenidate may exert effects on brain neurochemistry that modify some behaviors even in adulthood."