Different Dyskinesias in Parkinson's Disease and Their Relationship to Levodopa

Introduction

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the motor features of bradykinesia, tremor, and rigidity due in part to a loss of dopamine (DA) neurons in the nigrostriatal pathway. However, there is established evidence that other neurotransmitter systems such as the serotonergic system also display reduced innervation that may be responsible for the appearance of nonmotor symptoms also commonly seen in the clinical course of the disease.1–3 Nonetheless, the principal agents for treating PD are dopaminergic drugs (eg, levodopa and DA agonists), which are effective in relieving the motor symptoms of the disease. Unfortunately, long-term use of dopaminergic drugs often leads to motor complications such as on-off fluctuations and dyskinesia. The term levodopa-induced dyskinesia (LID) specifically refers to the motor complication arising from long-term use of levodopa.4 It appears that DA agonists are less likely to induce dyskinesia in PD patients compared to levodopa.5

Abstract

Levodopa is the principal agent in the treatment of Parkinson's disease (PD). Unfortunately the therapeutic benefits are optimal only in the early stages of the disease, with long-term use associated with motor complications such as levodopa-induced dyskinesia (LID). Risk factors associated with the development of LID are generally accepted to involve the degree of dopamine (DA) denervation in the nigrostriatal pathway, levodopa dose, and duration of levodopa treatment. Little is known regarding the underlying mechanisms of LID, although it is known that levodopa plasma concentrations are closely associated with the onset of some types of LIDs (peak-dose and biphasic dyskinesias) and it appears that increased DA turnover plays a crucial role in LID development. Recent evidence suggests that other cell types such as serotonin neurons possess the ability to convert levodopa into DA, subsequently storing and releasing it thereby increasing the levels of extracellular DA, exacerbating LID. This review will highlight the evidence to date from in vitro and in vivo studies utilizing both animal models and patients, regarding the relationship between levodopa treatment and the development of LID. Understanding the pathogenesis of LID is a therapeutic priority in tackling motor complications related to levodopa treatment in PD.

Keywords

Parkinson's disease, dyskinesia, levodopa, dopamine, serotonin