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Amphetamine-related drugs ameliorate symptoms of Parkinson's

PLOS



To model Parkinson's disease, researchers bred mice with severe dopamine deficiencies that displayed rigidity, inhibited motion, and, as seen here, freezing behavior. (Photo: Caron et al.)
Click here for a high resolution photograph.

The debilitating effects of Parkinson's disease are well known: muscle rigidity, impaired movement, and the uncontrollable shaking that makes even the most mundane activity a challenge. The symptoms result from a progressive deterioration of neurons, found in the midbrain, that produce dopamine. With no cure on the horizon, the most common treatment involves administration of the dopamine precursor, L-DOPA, usually in pill form. Though symptoms subside at first, this treatment is rendered ineffective over time.

In a new study reported in the open-access journal PLoS Biology, Tatyana Sotnikova and colleagues from Duke University create a mouse model that recapitulates many of the symptoms of Parkinson's disease and use it to screen potential therapeutic drugs. By eliminating the dopamine transporter - the protein responsible for recycling the chemical into neurons - in mice, the authors reduced dopamine levels in the midbrain by 20-fold. In addition, chemically inhibiting dopamine production in these mice resulted in essentially unmeasurable levels of the neurotransmitter, since it could now neither be produced at normal levels nor be recycled.

The authors tested a number of drugs at various doses and found that in addition to L-DOPA-related treatments, drugs related to amphetamine were effective in ameliorating muscle rigidity, tremor, and impaired movement in these mice. Most effective was methylenedioxymethamphetamine HCl (MDMA), commonly known as ecstasy. It has been shown that amphetamines can trigger release of neurotransmitters such as dopamine, serotonin, and norepinephrine and cause sudden bursts in neurotransmission, leading to a feeling of alertness, increased muscular activity, and reduced fatigue. This study, however, shows that treating mice with MDMA does not increase dopamine levels; furthermore, treating the mice with drugs related to serotonin or norepinephrine did not ameliorate the disease's symptoms. These results suggest that MDMA likely acts through a pathway unrelated to these common neurotransmitters.

Future work will be required to understand how MDMA was able to ameliorate the symptoms of Parkinson's in these mice and to assess the toxicity of MDMA and related compounds in greater detail in the future. However, this study opens the door to a search for compounds related to ecstasy, which may provide a more effective treatment in the later stages of the disease - and hopefully allow patients to perform the simple functions of everyday life independently again.

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Citation: Sotnikova TD, Beaulieu JM, Barak LS, Wetsel WC, Caron MG, et al. (2005) Dopamine-independent locomotor actions of amphetamines in a novel acute mouse model of Parkinson's disease. PLoS Biol 3(8): e271.

CONTACT:
Marc G. G. Caron
Duke University Medical Center
Rm 487 CARL Bldg, Research Dr.
Durham, NC USA 27710
+1-919-684-5433
+1-919-681-8641 (fax)
caron002@mc.duke.edu

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