In this project the team will explore a possible mechanism responsible for a common complication of long-term L-dopa treatment in Parkinson’s disease (PD), L-dopa induced-involuntary movements or dyskinesias. They believe that when many of the dopamine cells in the brain are dead or malfunctioning another set of brain cells called serotonergic neurones may take up L-dopa and transform it into dopamine, releasing the latter in an uncontrolled fashion, and this may cause or aggravate involuntary movements.
Project Description:The team will use a special brain scanner called Positron Emission Tomography (PET) to study groups of patients with and without dyskinesias. The patients will have a first scan with a specific radiochemical (tracer) called DASB to assess the integrity and functioning of their brain serotonergic innervation. They will then have brain scans called raclopride PET scans to evaluate their capacity to release brain dopamine after taking a dose of oral L-dopa and again following a dose of oral L-dopa and a drug that blocks sertonergic neurons working called buspirone. If seronergic nerves are releasing dopamine inappropriately buspirone should help to stop this happening. Patients will be also assessed clinically to evaluate their parkinsonian symptoms and the presence and severity of dyskinesia.
Relevance to Diagnosis/Treatment of Parkinson’s Disease: If the study is successful it will encourage the development of new and more selective drugs aimed to damp serotonergic function for the treatment of L-dopa-induced dyskinesias as the current available drugs including buspirone are not well suited to be used on a long term basis as they have sedative effects.
The team hypothesizes that following the challenge with L-dopa PD patients with dyskinesia will show a sudden increase in the levels of brain dopamine with appearance or worsening of dyskinesias. They also hypothesize that buspirone will then reduce the levels of brain dopamine generated from the serotonergic terminals after l-dopa administration and this will be associated with a reduction in dyskinesia intensity.