The researchers caution that the findings in animals do not suggest Parkinson's disease patients should find relief by taking amphetamines, which are drugs of abuse with many dangerous side effects. The findings rather indicate that drugs with similar chemical attributes might offer useful alternatives to current therapies, the researchers said.
The new study also shows that amphetamines -- normally thought to act by increasing dopamine concentrations in the brain -- correct the behavioral abnormalities associated with Parkinson's in mice devoid of the brain messenger. Dopamine normally acts on dopamine receptors -- protein switches on the surface of neurons -- to stimulate brain processes that affect movement, emotion, pleasure and mood.
Parkinson's disease stems from the degeneration of neurons in a brain region that controls movement. That degeneration, in turn, leads to a shortage of the chemical messenger dopamine. The finding that amphetamines can alter movement independently of dopamine opens up new directions in the search for prospective anti-Parkinsonian drugs, the researchers said.
The researchers, led by James B. Duke professor of cell biology Marc Caron, Ph.D. and Assistant Research Professor Raul Gainetdinov, M.D., Ph.D., of Duke, made the discovery after testing the utility of more than 60 compounds for reversing Parkinson's symptoms in a mouse model of the disease. Developed by the Duke team, the mice lack detectable brain levels of dopamine and experience essentially all the symptoms of Parkinson's disease for several hours before recovering their normal behavior. Caron is also a researcher of the Duke Institute for Genome Sciences & Policy.
The team reports its findings in the August 2005 issue of Public Library of Science (PLoS) Biology. The research was sponsored by the National Institutes of Health and a donation from The Long Island Community Foundation, a division of The New York Community Trust.
"This model is exciting because it allows us to examine the potential contribution of systems other than dopamine to Parkinson's disease," said Caron. "We may be able to discover avenues for treatment that had never been thought about before or that were impossible to investigate."
The new mouse model enables the researchers to acutely eliminate dopamine, exposing systems contributing to the disease that may not have been obvious before, he explained. The severity of disease symptoms in the mice also provides a very sensitive test for compounds with potential therapeutic value, the researchers said.
In the United States, at least 500,000 people suffer from Parkinson's disease, and about 50,000 new cases are reported annually, according to the National Institute of Neurological Disorders and Stroke. These figures are expected to rise as the average age of the population increases. Symptoms of the disease include tremors, slow movement or an inability to move, rigid limbs and a shuffling gait. Progression of the disease also leads to severe impairment in cognitive function.
Dopamine replacement therapy which involves administration of the dopamine precursor, L-DOPA, remains the gold standard for Parkinson's treatment, said Tatyana Sotnikova, Ph.D., of Duke. However, the efficacy of the therapy wanes with time, and patients often develop fluctuations in motor performance and other adverse reactions.
In the current study, the researchers treated mice unable to recycle dopamine with a drug that also prevented them from manufacturing the brain messenger. The brains of the mice therefore lack detectable levels of dopamine and the animals exhibit all the symptoms of Parkinson's disease for up to 16 hours. Those symptoms included severely impaired movement, rigidity and tremor. When treated with L-DOPA, the symptoms disappeared as the animals resumed normal movement.
Surprisingly, the researchers reported, treating mice lacking dopamine with high doses of amphetamine derivatives - including methamphetamine and MDMA, otherwise known as Ecstasy - reversed those symptoms. Ecstasy was most effective at counteracting the manifestations of Parkinson's symptoms in the mice, with the beneficial effects becoming more pronounced with increasing dose.
The researchers also report that low doses of amphetamines could, when combined with L-DOPA, potentiate minimally effective doses of L-DOPA in the mice. This could have important considerations in reducing some of the side effects of current therapy.
"The locomotor stimulating effect of amphetamine and its derivatives are classically thought to result from a massive flood of dopamine," said Sotnikova. "However, the mice have only a tiny fraction of dopamine, which cannot be recycled, precluding a rise in dopamine as the possible mechanism.
"Taken together, the findings indicate that Ecstasy can improve movement control independently of dopamine and, most importantly provide evidence that drug activation of other neuronal pathways may be sufficient to restore movement even in the virtual absence of dopamine neurotransmission," she added.
Amphetamines might reverse the animal's symptoms through their effects on a different group of receptors called trace amine receptors, the researchers suggested. Recent evidence showed that amphetamines act on trace amine receptors in addition to dopamine transmission, yet little is known about their physiological role in mammals.
The current findings are particularly promising given the severity of symptoms in the mice completely lacking dopamine, said Gainetdinov. "We think that this new animal model provides a much more stringent test for potential drugs that might prove efficacious in patients with Parkinson's disease."
Many of the previously developed animal models of Parkinson's disease have reduced, but detectable, levels of dopamine and do not show all the characteristics of Parkinson's disease, making studies of potential therapeutic methods in those animals less clear, Gainetdinov said. On the other hand, animals permanently lacking dopamine cannot survive, he added.
While the results are promising, the researchers cautioned, Ecstasy's ability to stimulate movement in the mice occurred only with high doses of the drug. Such high doses might destroy nerve tissue in normal mice and in humans, who are generally more sensitive than mice to such drugs.
"Amphetamines are controversial drugs, and there's no reason to suggest that amphetamines themselves should be used to treat Parkinson's," Gainetdinov said. "However, the chemical structure of amphetamines may lead to new, amphetamine-like drugs, that might provide a more lasting and beneficial alternative to L-DOPA in the treatment of Parkinson's disease."
Collaborators on the study include Jean-Martin Beaulieu, Larry S. Barak and William C. Wetsel all of Duke.