January 26, 2018

Nearly one million Americans live with Parkinson’s disease (PD). As the disease progresses, people who have PD are likely to lose motor functions and the ability to live an independent life. Much of this is attributable to the drug treatment for PD that leads to abnormal, involuntary movements known as dyskinesias. Scientists at Yerkes National Primate Research Center have been probing the origin of these abnormal responses to treatment and have successfully tested a tactic for controlling them.

Dyskinesias are believed to be caused by fluctuations in dopamine, the neurotransmitter whose production is lost in the brains of those with Parkinson’s. The standard drug levodopa restores dopamine, but sometimes, in the process of achieving symptom relief, dopamine levels become too high, and responses are unstable.

Researchers led by Stella Papa, a Yerkes researcher and associate professor of neurology at Emory University School of Medicine, showed striatal projection neurons (SPN), which become hyperactive when nearby dopamine-producing neurons degenerate, could be controlled by certain drugs, reducing the rate of unstable responses to dopamine that cause dyskinesias.

“Our focus was to prove SPN hyperactivity plays an important role and that glutamate signals are a major contributor,” says Papa. “Knowing this mechanism may serve to develop different therapeutic strategies: pharmacological treatments or gene therapies.”

Yerkes researchers tested whether the drug LY235959 (an NMDA receptor antagonist) or NBQX (an AMPA receptor antagonist) could control SPN hyperactivity and dyskinesia symptoms in Parkinson’s model monkeys. The nonhuman primate model of Parkinson’s uses the neurotoxin MPTP, which destroys dopamine-producing neurons. Both drugs interfere with signals by the neurotransmitter glutamate. In the presence of levodopa, the drugs had calming effects. After lowering the SPN firing frequency by 50 percent, the response to dopamine stabilizes and abnormal movements are markedly diminished.

The particular drugs used are not ideal for human application, but they do reveal mechanisms behind dyskinesias. Researchers say these insights will be valuable to advance their research and, ultimately, develop new treatments with improved effectiveness for people who have PD.

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