The serotonergic system in Parkinson's patients with dyskinesia: evidence from imaging studies

Abstract

The purpose of review is to review the current status of positron emission tomography (PET) molecular imaging of serotonergic system in Parkinson's patients who experience levodopa-induced (LIDs) and graft-induced dyskinesias (GIDs). PET imaging studies have shown that Parkinson's disease is characterized by progressive loss of dopaminergic and serotonergic neurons. Parkinson's patients who experienced LIDs and GIDs have an aberrant spreading of serotonergic terminals, which lead to an increased serotonergic/dopaminergic terminals ratio within the putamen. Serotonergic terminals convert exogenous levodopa into dopamine in a non-physiological manner and release an abnormal amount of dopamine without an auto-regulatory feedback. This results in higher swings in synaptic levels of dopamine, which leads to the development of LIDs and GIDs. The modulation of serotonergic terminals with 5-HT_1A and 5-HT_1B receptors agonists partially reduced these motor complications. In vivo PET studies confirmed that abnormal spreading of serotonergic terminals within the putamen has a pivotal role in the development of LIDs and GIDs. However, glutamatergic, adenosinergic, opioid systems, and phosphodiesterases 10A may also play a role in the development of these motor complications. An integrative multimodal imaging approach combining PET and MRI imaging techniques is needed to fully understand the mechanisms underlying the development of LIDs and GIDs.

Keywords: Graft-induced dyskinesias; Levodopa-induced dyskinesias; Molecular imaging; Parkinson’s diseases; Positron emission tomography; Serotonergic system.

Fig. 1

Involvement of the serotonergic system in the development of levodopa-induced dyskinesia. Illustration of the striatal serotonergic and dopaminergic innervation in healthy subjects (a), Parkinson’s patients with stable response to levodopa (b), and Parkinson’s patients who experiences levodopa-induced dyskinesias (c). a Healthy subjects showed normal dopaminergic and serotonergic terminals. b Parkinson’s patients with stable response to levodopa show loss of dopaminergic and serotonergic terminals. The remaining dopaminergic terminals reuptake dopamine through DAT and store it at pre-synaptic level. Serotonergic terminals do not release dopamine excessively after levodopa supplementation. As a consequence, dopamine levels remain relatively stable in the synaptic cleft and patients have a stable response to levodopa. c Parkinson’s patients who experience levodopa-induced dyskinesias show dramatic loss of dopaminergic terminals; however, the loss of serotonin terminals has not achieved such a critical low. The few remaining dopaminergic terminals lack the capacity to store dopamine and fail to reuptake dopamine through DAT. The serotonergic terminals try to compensate to the loss of dopaminergic terminals by handling the uptake and release of dopamine in the synapse. However, serotonergic terminals release dopamine in an excessive and inappropriate manner after levodopa supplementation, due to a lack of an auto-regulatory feedback for dopamine release in serotonergic neurons. As a consequence, there is a sharp and dysregulated increase of dopamine levels in the synaptic cleft, which is associated with the development of levodopa-induced dyskinesias. c Summed [¹²³I]FP-CIT SPECT and [¹¹C]DASB PET images coregistered and fused with 3T MRI images at the level of the dorsal basal ganglia for a healthy subject with normal dopaminergic and serotonergic innervation (d), a Parkinson’s patient with stable response to levodopa with loss of serotonergic and dopaminergic innervation (e), and a Parkinson’s patient who experiences levodopa-induced dyskinesia with a loss of dopaminergic innervation but preserved serotonergic innervation (f). DAT dopamine transporter, SERT serotonin transporter, FP-CIT SPECT ligand with high selectivity for DAT, DASB PET ligand with high selectivity for SERT