Investigators eye new target for treating movement disorders

January 19, 2018 by Bill Snyder, Vanderbilt University

Blocking a nerve-cell receptor in part of the brain that coordinates movement could improve the treatment of Parkinson's disease, dyskinesia and other movement disorders, researchers at Vanderbilt University have reported.

Their findings, published recently in the journal Neuron, focus on M4, a subtype of the muscarinic acetylcholine family of nerve cell (neuron) activated by binding the neurotransmitter acetylcholine.

The Vanderbilt scientists found that M4 neurons project into the substantia nigra pars reticulata, a small structure near the base of the brain important in regulating movement. Here M4 receptor activation opposes signaling by another class of receptors that binds the .

When, in Parkinson's , -producing neurons begin to die off, the opposing action of M4 neurons can suppress dopamine signaling even further.

Drugs called M4 selective antagonists, which selectively block the M4 receptor, thus may relieve symptoms of the disease.

"M4 muscarinic receptor activation has a much more pivotal role in controlling dopamine signaling than we thought," said the paper's corresponding author, P. Jeffrey Conn, Ph.D.

This finding "gives much greater strength to the notion that we could use M4 selective antagonists to treat Parkinson's disease," he said.

Drugs that block muscarinic acetylcholine receptors can relieve symptoms of Parkinson's disease including tremors and muscle rigidity. But because they block the whole muscarinic acetylcholine family of receptors, these drugs cause adverse side effects patients can't tolerate, said Conn, who directs the Vanderbilt Center for Neuroscience Drug Discovery.

For years L-DOPA, a precursor to dopamine that can replenish the brain's supply of the neurotransmitter, has been the main treatment for Parkinson's disease. But L-DOPA is not without its side effects, either.

The identification of different subtypes of the muscarinic acetylcholine receptor raised the possibility of selectively targeting treatment in a way that avoids unwanted side effects.

Conn and his colleagues have been developing potential drugs called positive allosteric modulators that can boost the activity of the M4 receptor like the dimmer in an electrical circuit.

"In schizophrenia there's excessive dopamine transmission," he said. "We've studying M4 as a way to dampen dopamine function in schizophrenia patients. It's actually those studies that led us to develop these insights into M4 regulation of dopamine signaling" in movement disorders.

"We used genetic approaches and now have very selective compounds that have anti-parkinsonian activity in animal models," said Conn, the Lee E. Limbird Professor of Pharmacology in the School of Medicine.

"We've shown that with the first one. Now we have much better compounds that we're going to follow."

Explore further: Researchers eye potential schizophrenia 'switch'

Related Stories

Researchers eye potential schizophrenia 'switch'

September 19, 2016
Researchers at Vanderbilt University Medical Center have discovered a key mechanism that explains how compounds they're developing can suppress schizophrenia-like symptoms in mice without side effects.

Intracellular dopamine receptor function may offer hope to schizophrenia patients

December 9, 2016
Dopamine is a chemical in the brain that plays an important role in controlling movement, emotion and cognition. Dopamine dysfunction is believed to be one of the causes of disorders like Schizophrenia, Tourette's syndrome, ...

Parkinson's treatment could be more effective, student finds

January 4, 2018
A Binghamton University senior and her colleagues recently uncovered evidence that the current treatment for Parkinson's disease may not be as effective as it could be.

Dopamine receptor blockade seen as cause for antipsychotic drug side-effects

July 6, 2016
Since their development in the 1950s, antipsychotic drugs have been widely used to treat psychoses and neuropsychiatric disorders like schizophrenia. A debilitating side-effect of these drugs called parkinsonism limits their ...

Scientific discovery may change treatment of Parkinson's disease

March 22, 2017
When monitoring Parkinson's disease, SPECT imaging of the brain is used for acquiring information on the dopamine activity. A new study conducted in Turku, Finland, shows that the dopamine activity observed in SPECT imaging ...

Recommended for you

Researchers find inhibiting one protein destroys toxic clumps seen in Parkinson's disease

November 14, 2018
A defining feature of Parkinson's disease is the clumps of alpha-synuclein protein that accumulate in the brain's motor control area, destroying dopamine-producing neurons. Natural processes can't clear these clusters, known ...

Scalpel-free surgery enhances quality of life for Parkinson's patients, study finds

November 9, 2018
A high-tech form of brain surgery that replaces scalpels with sound waves improved quality of life for people with Parkinson's disease that has resisted other forms of treatment, a new study has found.

Singing may reduce stress, improve motor function for people with Parkinson's disease

November 7, 2018
Singing may provide benefits beyond improving respiratory and swallow control in people with Parkinson's disease, according to new data from Iowa State University researchers.

Scientists overturn odds to make Parkinson's discovery

November 7, 2018
Scientists at the University of Dundee have confirmed that a key cellular pathway that protects the brain from damage is disrupted in Parkinson's patients, raising the possibility of new treatments for the disease.

Road to cell death more clearly identified for Parkinson's disease

November 1, 2018
In experiments performed in mice, Johns Hopkins researchers report they have identified the cascade of cell death events leading to the physical and intellectual degeneration associated with Parkinson's disease.

Appendix removal is linked to lower risk of Parkinson's

October 31, 2018
Scientists have found a new clue that Parkinson's disease may get its start not in the brain but in the gut—maybe in the appendix.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.