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Amphetamines Reverse Parkinson’s Disease Symptoms in Mice

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Duke Health News 919-660-1306

Durham, N.C. -- Amphetamines, including the drug popularly
known as Ecstasy, can reverse the symptoms of Parkinson's
disease in mice with an acute form of the condition, according
to new research at Duke University Medical Center.

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.

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