Objective/Rationale:
Our group has previously shown that brain cells that normally produce serotonin, by taking up L-dopa and then releasing dopamine in an uncontrolled fashion, play a crucial role in the development of L-dopa induced-dyskinesia. However, this process is likely to be just a part of a complex puzzle. In this project we will explore the hypothesis that both dopamine and serotonin neurons and their interaction with each other contribute to the development of Ldopa-induced involuntary movements.
Project Description:
By using special brain imaging techniques called single photon emission computed tomography (SPECT) and positron emission tomography (PET) we will study in vivo the function of dopamine and serotonin neurons in Parkinson’s disease (PD) patients with different types and severities of involuntary movements and compare the data with those from healthy subjects and PD patients who do not suffer from this side-effect. For this purpose we intend to make use of a large amount of imaging data that has been acquired previously in our unit and also to obtain a new dataset. Moreover, we will conduct an acute clinical trial where PD patients with dyskinesia will be receiving either doses of buspirone, a drug tested to improve dyskinesia, or placebo. Depending on the results of the acute trial, patients will continue to a long-term trial, which will imitate a drug prescription used in daily life.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If our study is successful it will help to understand the mechanisms involved in the development of L-dopa induced-dyskinesia in PD. It will also support the use of buspirone and encourage the development of similar but more specific new drugs to improve the management of this troublesome side effect of chronic L-dopa therapy.
Anticipated Outcome:
We hope to clarify further the role of serotonergic cells and whether dopaminergic mechanisms interact with serotonergic mechanisms in the development of L-dopa induced involuntary movements in PD. We hypothesize that these interactions are crucial in the development of dyskinesia. Furthermore, we expect to determine whether different doses of a drug acting on the serotonin receptor 1A will interfere with these mechanisms and as a result attenuate the involuntary movements.
Progress Report
We are currently investigating the role of serotonergic and dopamineric mechanisms and their interactions in the development of levodopa-induced dyskinesia in patients with Parkinson’s disease. We are using imaging techniques such as Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) with specific markers to assess in vivo in the basal ganglia of PD patients the availability and density of dopamine D2 receptors, serotonergic transporter and dopamine transporter. So far, we have been able to show that the abnormal release of dopamine by striatal serotonergic terminals is associated with dyskinesia and also that this mechanism appears to be more relevant in mild rather than severe dyskinesia. We hope to further demonstrate that the striatal ratio of serotonergic and dopaminergic terminals, with the availability status of D2 receptors, are an important determinant in the development of dyskinesia.
Presentations & Publications
An abstract entitled “Serotonergic mediated peak-dose L-DOPA-induced dyskinesias in Parkinson’s disease” was accepted for platform presentation at the International Movement Disorder meeting in Dublin, 2012.