For most people with Parkinson's disease, the only relief from the tremors, rigidity and impaired movement associated with the progressive loss of their motor skills is a drug called L-DOPA. But as the disease progresses, L-DOPA can cause prominent side effects that counteract its effectiveness.
Now, Rockefeller University's Paul Greengard and colleagues at the Karolinska Institute in Sweden provide evidence that serotonin, a well-studied neurotransmitter involved in regulating mood, appetite, sexuality and sleep, also plays a crucial role in Parkinson's disease. Using a mouse model of the disease, Greengard's team shows that side effects associated with repeated L-DOPA treatment can be blocked by manipulating a specific serotonin receptor. The finding, reported this week in Proceedings of the National Academy of Sciences Early Edition online, points to a new target for developing treatments for this disorder, which is the second most common neurodegenerative disease after Alzheimer's.
“Our study provides a scientific rationale for developing drugs that act on the serotonin 1B receptor for the treatment of advanced Parkinsonism,” says senior co-author Per Svenningsson, a visiting professor in Greengard's lab and a group leader at the Karolinska Institute in Sweden.
The neurotransmitter dopamine has several functions in the brain, including the regulation of movement. Parkinson's disease is characterized by a progressive degeneration of dopamine-producing neurons, which causes tremors, rigidity and lack of movement control. These neurons project from the midbrain to an area of the brain called the corpus striatum. Although dopamine signaling is impaired in Parkinson's patients, serotonin production remains strong. In addition, several serotonin receptors are highly expressed in the striatum and available to modify the action of L-DOPA.
Two years ago, Greengard and Svenningsson identified a protein, called p11, that acts as a regulator of serotonin signaling in the brain. The researchers showed that p11 increases the concentration of the serotonin 1B receptor at synapses, thereby increasing the efficiency of serotonin signaling, and linked this interaction to an individual's susceptibility to depression and his or her response to antidepressant treatments.