Presynaptic Mechanisms of l-DOPA-Induced Dyskinesia: The Findings, the Debate, and the Therapeutic Implications.

M Angela Cenci

doi:10.3389/fneur.2014.00242

Abstract

The dopamine (DA) precursor l-DOPA has been the most effective treatment for Parkinson’s disease (PD) for over 40 years. However, the response to this treatment changes with disease progression, and most patients develop dyskinesias (abnormal involuntary movements) and motor fluctuations within a few years of l-DOPA therapy. There is wide consensus that these motor complications depend on both pre- and post-synaptic disturbances of nigrostriatal DA transmission. Several presynaptic mechanisms converge to generate large DA swings in the brain concomitant with the peaks-and-troughs of plasma l-DOPA levels, while post-synaptic changes engender abnormal functional responses in dopaminoceptive neurons. While this general picture is well-accepted, the relative contribution of different factors remains a matter of debate. A particularly animated debate has been growing around putative players on the presynaptic side of the cascade. To what extent do presynaptic disturbances in DA transmission depend on deficiency/dysfunction of the DA transporter, aberrant release of DA from serotonin neurons, or gliovascular mechanisms? And does noradrenaline (which is synthetized from DA) play a role? This review article will summarize key findings, controversies, and pending questions regarding the presynaptic mechanisms of l-DOPA-induced dyskinesia. Intriguingly, the debate around these mechanisms has spurred research into previously unexplored facets of brain plasticity that have far-reaching implications to the treatment of neuropsychiatric disease.

Highlights

The dopamine (DA) precursor L-DOPA has been the most effective treatment for Parkinson’s disease (PD) for over 40 years
Other microdialysis studies were performed in 6-OHDA-lesioned rats that had been chronically treated with a lower dose of l-DOPA (6 mg/kg/day), upon which some of the animals remained free from abnormal involuntary movements (AIMs)
Striatal levels of [11C]-DASB binding did not differ between the severely dyskinetic patients and the subjects with a stable response to therapy, who had a significantly shorter disease duration [102]. These results are at variance with the expected loss of [11C]-DASB binding during the progression of PD [92], and may suggest that serotonin axon terminals mount a long-term sprouting response in human l-DOPA-induced dyskinesia (LID), analogous to that seen in the animal models. Further support to this interpretation comes from an autoradiographic study of serotonin transporter (SERT) radioligand binding density in the human post-mortem putamen and pallidum, showing larger SERT binding levels in PD patients with clinical records of LID compared to non-dyskinetic cases [80]

Summary

Introduction

The dopamine (DA) precursor L-DOPA has been the most effective treatment for Parkinson’s disease (PD) for over 40 years. Autoradiographic studies of DAT binding in the post-mortem striatum have not detected a difference between dyskinetic and non-dyskinetic PD cases [42, 43], indicating that a severe dopaminergic denervation is not sufficient for some patients to develop LID. Other microdialysis studies were performed in 6-OHDA-lesioned rats that had been chronically treated with a lower dose of l-DOPA (6 mg/kg/day), upon which some of the animals remained free from AIMs. These studies reported larger striatal levels of l-DOPA [71] or DA

Results

Conclusion