Sci. Aging Knowl. Environ., 10 August 2005
Up to Speed
Amphetamines spare mice from Parkinson's disease-like symptoms
Mice are already jittery, so giving them amphetamines might seem superfluous. But a new study suggests that Ecstasy--one type of amphetamine--can restore movement in mice suffering symptoms similar to those of Parkinson's disease (PD). The work hints that the brain carries back-up circuits for controlling movement and might help scientists develop new drugs to combat the incurable disease.
PD results from the death of neurons that supply the brain with the neurotransmitter dopamine. Patients lose muscle control, developing symptoms such as tremors, rigid limbs, and a frozen facial expression (see Parkinson's Disease Case Study). The standard PD treatment is the compound L-dopa, which the brain converts to dopamine. But L-dopa gradually loses its power and can trigger erratic movements. Researchers seeking alternatives want to determine whether they can get patients moving again by spurring neural circuits that don't rely on dopamine. But such studies have run into an obstacle: Rodents without the neurotransmitter die young. So biochemist Marc Caron of Duke University Medical Center in Durham, North Carolina, and colleagues created mice that lack dopamine for only a short time.
After a neuron releases dopamine, a molecule called the dopamine transporter returns the neurotransmitter to the cell for reuse. Caron and colleagues engineered mice to lack the gene for this transporter. The rodents' neurons harbor only about 5% as much dopamine as normal, but the animals live to adulthood. The researchers temporarily banished the remaining dopamine from these mice with a compound that blocks the dopamine-making enzyme. Within a few minutes, the rodents began showing PD-like symptoms, such as paralysis and tremors. The animals became so stiff that the researchers could hang them by their feet from a horizontal wire, and they wouldn't fall off. After about a day, the rodents "unfroze." Next, the researchers tested a long list of compounds to determine whether any could speed recovery. Most failed. A few amphetamines alleviated some symptoms, but only the amphetamine derivative MDMA, better known as Ecstasy, allowed the mice to scurry again. Restoring movement required a huge dose of MDMA, but combining it with L-dopa reduced that amount. Overall, the findings suggest that the rodents sport movement-controlling neural circuits that don't need dopamine, says Caron. However, the researchers aren't sure what neurotransmitter incites these neurons. The results don't mean that PD patients should try to score speed on street corners, Caron cautions. But testing whether amphetamines benefit patients with the most severe symptoms might be worthwhile, he says.
PD researchers have traditionally focused on discovering ways to save dopamine, says neuroscientist Julie Andersen of the Buck Institute for Age Research in Novato, California. But the results might point toward alternative solutions, she says. If confirmed, the findings would force researchers to rethink whether dopamine is essential for movement, says neuroscientist David Sulzer of Columbia University in New York City. However, he notes, amphetamines can prod cells to make dopamine. To solidify the study's conclusion, he says, researchers need to verify that this extraneous dopamine isn't responsible for the animals' recovery. That work might reveal whether PD patients should be high on these findings.
August 10, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150