Background: Levodopa, the most commonly used medication for patients with Parkinson's disease, is a beneficial therapy, but as the disease progresses it can be the cause of debilitating involuntary movements, so-called dyskinesias. The effects of levodopa, both positive and negative, are caused by its conversion to dopamine in the brain. In patients with moderately advanced disease, the conversion to dopamine takes place mainly in the remaining dopamine neurons and their axon terminals in the striatum. As the disease progresses, and fewer and fewer dopamine terminals survive, another system kicks in: the seratonin neurons. The serotonin neurons and their axonal terminals in the striatum are capable of converting levodopa to dopamine, and store and release the newly synthesized dopamine in a physiological manner. The seratonin system is known to be affected in PD, but the extent of seratonin neuron degeneration varies from patient to patient. The role of seratonin neurons is in the development of dyskinesias is particularly interesting since they not only are capable of decarboxylating levodopa to dopamine, but also provide additional sites for storage and release of dopamine in advanced PD patients.
Purpose: The goal of the present project is to investigate in further detail the role of the residual serotonin innervation in the induction and maintenance of levodopa-induced dyskinesias. In a pilot experiment we have made the interesting observation that transplants of seratonin neurons will provide an almost complete protection against the development of levodopa-induced dyskinesias in parinsonian rats. In the present experiments we will study the role of striatal serotonin innervation in the synthesis and release of dopamine from systemically administered levodopa and in the development of levodopa-induced dyskinesias in the rat Parkinson model.
Significance: In advanced PD patients the seratonin innervation may act as a dopamine buffer and hence reduce the risk of developing dyskinesias. If so, concomitant degeneration of the dopamine and serotonin innervation of the striatum may make PD patients particulatly sensitive to develop dyskinesias. This may have important implications for the design of cell replacement therapy in PD: the fetal tissue used for transplantation is known to contain serotonin neurons, but their number will vary greatly depending on the dissection used. Our preliminary findings indicate that the serotonin neurons contained in the fetal tissue grafts may be effective in blocking the development of levodopa-induced dyskinesias. A better insight into the role of serotonin neurins in the induction and maintenance of dyskinesia may assist in the development of an improved cell transplantation protocol that will provide maximal clinical benefit in the absence of any dyskinetic side effects.
Dr. Bjorklund found that lesioning of the serotonin system can abolish levodopa-induced dyskinesias in a rodent PD model, an effect mimicked by serotonin receptor-targeted drugs. The serotonin system did not appear to play any role in the beneficial effects of levodopa. Dr. Bjorklund then received supplemental funding to test his theory in tissue transplants in other relevant models of Parkinson's. Transplants of different cell compositions (dopamine neurons only, serotonin neurons only or mixed) were tested for the ability to induce graft-induced dyskinesias.