Parkinson's disease (PD), a condition characterized by muscle stiffness and uncontrollable shaking, is caused by the progressive degeneration of midbrain neurons that control motor function. These neurons produce the neurotransmitter dopamine (DA), which has long been associated with motor function. As the neurons deteriorate, dopamine levels plummet, eventually leading to the symptoms of this debilitating disease. To understand the pathological processes leading to PD, researchers have developed rodent models that either recapitulate the loss of DA or recapitulate the neurodegenerative process. But many of these models only achieve incomplete DA depletion, often precluding an accurate recapitulation of the neurological manifestations of PD. Now, Tatyana Sotnikova and colleagues have successfully induced a reliable but transient recapitulation of PD symptoms in mice.
Normally, neurons have a large intracellular storage pool of DA. After its release, DA is rapidly recycled back into neurons' dopaminergic terminals by the dopamine transporter (DAT). To create their new PD model, the team knocked out the dopamine transporter in a group of mice, creating DAT-KO mice that have virtually no intracellular DA stores. Unlike normal mice, which have plenty of dopamine in storage, DAT-KO mice depend upon the DA produced by ongoing synthesis. So, by blocking DA synthesis in these mice, the team could now eliminate all DA in these animals. When they administered the DA synthesis inhibitor αMT to the DAT-KO mice, the animals immediately showed reliable symptoms of PD; they became immobile and displayed extreme rigidity,body tremors and droopy eyelids. Now that the team had successfully created a mouse model of PD, they set out to identify drugs that could relieve the symptoms of PD. They first tested the effects of administering l-DOPA, a DA precursor that is commonly given to PD patients, to DAT-KO mice. They discovered that l-DOPA is just as effective in mice as it is in humans in the early stages of PD; the drug successfully restored locomotion in DAT-KO mice. Testing several amphetamine derivatives,the authors discovered that MDMA (better known as ecstasy) also restored movement control sufficiently to allow the mice to move forwards. Since amphetamines are thought to act through the dopamine system to affect movement, this was a surprising result, because the team was unable to detect measurable DA levels in the midbrain neurons of these mice. They conclude that ecstasy must be acting through an unknown DA-independent mechanism. When the team paired a lower dose of ecstasy with a minimally effective l-DOPA dose, a synergistic effect occurred: it caused the same effect as a higher dose of either ecstasy or l-DOPA alone. Thus,the DA-independent locomotor effect of ecstasy can be markedly enhanced with additional DA stimulation.
It is currently unclear how this synergistic effect occurs, but amphetamines can clearly affect neuronal systems involved in motor control through mechanisms independent of dopamine. Amphetamines interact with proteins called trace amine receptors, and the authors suggest this interaction as a possible mechanism. Since very little is known about the physiological role of these receptors, more research is needed to delineate the DA-independent mechanism of amphetamines in locomotion. But in the search for new treatments for Parkinson's disease, this study certainly offers a glimmer of hope.
