Recently, a group of researchers from the Columbia University Medical Center (CUMC), in New York, have identified the physiological reason why dyskinesias, the involuntary motor movements experienced by patients with Parkinson’s disease (PD) who are treated with levodopa, occurs. The study, entitled, “Loss of Striatonigral GABAergic Presynaptic Inhibition Enables Motor Sensitization in Parkinsonian Mice,” was published in the latest edition of the journal Neuron.
To investigate why dyskinesias occur the researchers used a new experimental technique called optogenetics in which light is used to control motor neurons in mice with PD, this way determining how motor neurons within the basal gangia (structures in the brain that control movement) regulate movement in the absence of the neurotransmitter dopamine.
The findings showed that after long-term dopamine loss, certain neurons loose their ability to respond to the neurotransmitter GABA (gamma-aminobutyric acid). This effect was not found upon short-term dopamine loss in the animal model.
In a University press release on the study’s findings, Dr. David L. Sulzer, PhD, professor of neurobiology, Departments of Neurology, Psychiatry, and Pharmacology, CUMC, research scientist, New York State Psychiatric Institute, and senior study author, explained, “While Parkinson’s is not curable, it is treatable with L-DOPA, which is converted into dopamine in the brain. However, while taking L-DOPA helps patients move normally, in many individuals it eventually triggers uncontrolled excessive movements. When striatonigral neurons are working normally, they act as a brake on the basal ganglia, in effect shutting down unwanted movement. But when there is dopamine loss, as in Parkinson’s, striatonigral neurons try to compensate, and eventually lose their responsiveness to GABA. Our hypothesis is that when L-DOPA is added into the system, you lose the ability to filter, or turn off, unwanted movement.”
Dr. Sulzer’s colleague and lead study author, Dr. Anders Borgkvist, Phd, stated “Our findings suggest that GABA and GABA receptors are still present in the striatonigral neurons. So then the question becomes, why they aren’t functional? I think that we, or another lab, will eventually find the answer. In any case, the implication is that this defect is correctable, and that would mean that we could prevent or at least delay dyskinesia, so that patients could continue to use L-DOPA.”
Dr. Borgkvist’s opinion is shared by Dr. Stanley Fahn, MD, the H. Houston Merritt Professor of Neurology and emeritus director of the Parkinson’s Disease Foundation Research Center at CUMC, who said, “Patients do not develop dyskinesias in the early stages of Parkinson’s, but only after several years of the disease. A major reason why these patients want to delay the initiation of L-DOPA therapy is to avoid these dyskinesias for as long as possible. These new findings open up possible ways to treat or prevent the dyskinesias. If such treatments were found, patients would probably seek to be treated early and improve their quality of life sooner.”