New research on Parkinson disease (PD) has yielded both a promising new mouse model for acute disease and the surprising finding that potential therapeutic compounds might be found among members of the amphetamine family, such as Ecstasy.

The effects of PD are gradual but devastating. Dopamine (DA) responsive neurons in locomotor centers of the brain die as a result of pathological mechanisms that still are not entirely well understood, and once this cell population drops below a critical threshold, the patient is subject to an array of debilitating physical symptoms that can include stiffness, tremor, and slowness of movement. There is only a limited range of pharmacological therapeutic options; compounding this problem has been the difficulty in generating relevant animal models for the disease, and mice have generally proven inadequate for the detailed study of DA-related locomotor disorders.

Marc Caron and his colleagues at the Duke University Medical Center (Durham, NC) had previously developed DAT-KO, a mouse strain deficient in the dopamine transporter (DAT), a protein essential for maintaining functional reserves of neurotransmitter. Now, in a new article from PLoS Biology (August), they show that by treating these DAT-KO mice with a compound that inhibits DA synthesis, it becomes possible to transiently establish conditions of extremely low DA—as low as 1 or 2% of control levels—and generate behavioral phenotypes that very closely resemble the symptoms of PD.

The depletion takes place rapidly and lasts as long as 16 hours, during which time the treated DAT-KO mice displayed a dramatic reduction in locomotion, body rigidity, and tremor. By comparison, wild-type mice treated with identical drug dosages showed no symptoms. The authors indicate that this highlights the importance of DA reservoirs—maintained through the action of DAT—for maintaining normal locomotor function even while DA synthesis is being modulated.

The authors recognized the potential of this model for determining the efficacy of treatments for acute PD and proceeded to test a variety of compounds. As expected, L-DOPA, a natural DA precursor and popular treatment for PD, considerably ameliorated symptoms in these mice. Surprisingly, the authors found that amphetamine derivatives, which act via distinct and DA-independent signaling pathways, also showed some therapeutic benefits. In particular, MDMA—better known as Ecstasy—had a profound impact at high doses, restoring considerable locomotor activity to affected mice. These MDMA doses are too high to be considered practical for therapy, but this work suggests a new and potentially very valuable template for the design of future PD therapeutics—and a useful animal model in which to test them.