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Neurology Today:
doi: 10.1097/01.NT.0000314564.58506.3c
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Serotonin Plays a Role in Parkinson Disease Symptoms

Talan, Jamie

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ARTICLE IN BRIEF

✓ Investigators identified a new important player — serotonin — in Parkinson disease, showing that this neurochemical may actually inhibit dyskinesias, which often develop after chronic use of levodopa.

Dopamine has always been the dominant chemical in the neurobiology of Parkinson disease. Symptoms emerge when the disease is well under way because more than 80 percent of the dopamine-containing cells are already damaged or dead. After all, the loss of cells in the dopamine-rich substantia nigra is obvious and these are the cells that die off.

Now, Nobel laureate Paul Greengard, PhD, the Vincent Astor Professor and head of the Laboratory of Molecular and Cellular Neuroscience of Rockefeller University and collaborators at the Karolinska Institute in Stockholm, have identified a new important player — serotonin — showing that this neurochemical may actually inhibit dyskinesias that often develop after chronic use of levodopa. The findings were published in the Feb.12 edition of the Proceedings of the National Academy of Sciences.

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Experiments in Mice

Two years ago, Dr. Greengard and his colleague Per Svenningsson, MD, PhD, a visiting professor in the Greengard lab at Rockefeller and associate professor at the Karolinska Institute, identified a protein called p11 that regulates serotonin signaling in the brain. The protein increases the number of serotonin receptors at the synapse, making signaling more efficient. Some evidence suggests that the level of p11 may be linked to a person's susceptibility to depression and, if so, may eventually help predict whether a person would respond well to antidepressant treatment.

In the latest study, the investigators found that p11 and serotonin play a role in the dyskinesias, which can follow chronic use of levodopa. They used a toxic substance called 6-hydroxydopamine (6-OHDA) to destroy dopamine neurons in the same region that is hit hard in PD. But they only targeted one side of the brain. When they fed the animals levodopa, the animals rotated their bodies away from the damaged hemisphere. And when they examined the brains of the animals fed levodopa, they found increased levels of serotonin 1B receptor and p11 in the striatum.

Figure. Dr. Paul Gre...
Figure. Dr. Paul Gre...
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Based on these results, the scientists used a serotonin agonist in another series of studies in PD mice. They also tested the serotonin agonists in mice whose dopamine neurons in the striatum were destroyed and who were bred without the p11 protein.

The rotational behavior and involuntary movements improved in the mice fed serotonin agonists, but had no effect on movement in the p11 knockout mice. This, said Dr. Svenningsson, suggests that serotonin agonists work through p11 to prevent dyskinesias.

If a similar process occurs in humans, serotonin agonists might be used to treat advanced PD when levodopa is no longer working or is causing side effects.

“Developing compounds that target the serotonin 1B receptor may offer an alternative approach for treating advanced Parkinson disease,” Dr. Greengard said.

The investigators suspect that the serotonin agonists worked by reducing the release of GABA (gamma-amino butyric acid). The inhibitory chemical is released from neurons that contain the dopamine 1 receptor.

They also reported that levodopa increases the amount of p11 in the brain. Although serotonin is not altered in PD, serotonin innervates the striatum. This relationship could explain why as many as 50 percent of PD patients develop depression.

The investigators theorize that lowered levels of p11 in PD patients may contribute to the relatively high incidence of comorbid depression. “We are currently investigating this hypothesis,” Dr. Svenningsson said. The p11 protein might also be a good biomarker to predict vulnerability for depression in PD patients.

Figure. Dr. Per Sven...
Figure. Dr. Per Sven...
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The researchers gave mice enough levodopa to trigger dyskinesias, and found increased levels of the serotonin 5-HTIB receptor and p11 in dopamine-denervated striatal neurons.

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A ‘New Alternate Player’

“Despite the multiple pharmacological manipulations of dopamine, the therapeutic benefit of Parkinson disease remains suboptimal,” said Mark Gudesblatt, MD, a neurologist at South Shore Neurologic Associates on Long Island.

Dr. Gudesblatt, a PD expert, said PD has been described as a ‘dopamine deficiency disorder,’ but Dr. Greengard and colleagues have now clearly “demonstrated that not only is this incorrect, but there are several new possible partners in the previous solitary PD-dopamine dance.”

Scientists and doctors have been frustrated by a lack of treatments that delay the side effects of levodopa. “These new alternative players will next be explored and manipulated in the same manner that has been done for dopamine,” Dr. Gudesblatt said. “This will ultimately allow additional novel opportunities for improved understanding of both PD progression and variation, and most importantly, will result in exciting new therapeutic options for those with PD.”

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REFERENCE

• Zhang X, Greengard P, Svenningsson P, et al. Evidence for a role of the 5-HT1B receptor and its adaptor protein, p11, in L-DOPA treatment of an animal model of Parkinsonism. Proc Natl Acad Sci 2008; 105(6):2163–2168.

©2008 American Academy of Neurology

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