Sci. Aging Knowl. Environ., 3 September 2003
Stimulated to Death
Excess dopamine slays movement-controlling neurons in the brain
Key Words: dopaminergic neurons dyskinesia astrocytosis TUNEL assay apoptosis
Listening to your teenager's stereo blaring the same song all day only seems like it's destroying your brain. However, some kinds of overstimulation can wreck neurons, according to a new study. Brain cells kill themselves after incessant prodding by the neurotransmitter dopamine. The work uncovers a new mechanism of neural degeneration and might explain what triggers one of the most common side effects of Parkinson's disease (PD) treatment.
The tremors and rigid muscles of PD result from a dopamine shortage. But too much of the compound is a problem too. Several studies of rodents suggest that large amounts of the messenger wound dopamine-releasing neurons in a brain region called the substantia nigra. However, scientists don't know whether excess dopamine damages cells elsewhere in the brain. Biochemist Marc Caron of Duke University Medical Center in Durham, North Carolina, and colleagues became interested in the possibility after observing mice that were genetically engineered to lack a molecule that recycles dopamine. In the rodents, the part of the brain called the striatum, which helps control movement, brims with about five times the normal amount of the molecule; the dopamine was produced by the substantia nigra as usual. The animals stumble, develop hunched backs, become lethargic, and tend to die young.
The researchers verified that excess dopamine spurs this decline. A mouse dangled by the tail normally splays its legs, but an animal with neural deterioration bunches all four paws together--a behavior called clasping. Using clasping as an indicator of brain condition, the researchers curtailed dopamine production in some of the engineered mice by blocking an enzyme that helps make it. Mice that received only saline clasped more often than the treated rodents did, bolstering the notion that an oversupply of dopamine somehow spurs brain decay.
To find out how, the team tested tissue from the striatum. Compared with samples from normal controls, samples from the engineered mice carried nearly 30% fewer cells and held broken DNA and remnants of a protein that spurs cell suicide, suggesting that the excess dopamine was inducing neurons to end it all. The researchers observed no die-off of dopamine-releasing neurons, only carnage among the dopamine-receiving cells. This specificity suggests that dopamine doesn't wreck cells indiscriminately by oxidizing them, as many researchers thought, but selectively harms its target neurons by overstimulating them and triggering their suicide, says Caron.
"I was very impressed by their broad approach," which combines data from behavioral, cellular, and molecular experiments, says neurochemist Paul Garris of Illinois State University in Normal. The findings could clarify the cause of a cruel PD side effect, he says. To replace their lost dopamine, PD patients take the drug L-dopa, which the brain transforms into dopamine. However, after several years, many patients begin to suffer jerky, violent movements. Perhaps excess dopamine from the treatment kills cells in the striatum that smooth movement, he says. Further research might reveal treatments to break the molecular chain of events that links excess dopamine to cell death, he adds. Turning down the dopamine volume might spare the brain.
September 3, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150