Abstract
L-DOPA is the criterion standard of treatment for Parkinson disease. Although it alleviates some of the Parkinsonian symptoms, long-term treatment induces L-DOPA–induced dyskinesia (LID). Several theoretical models including the firing rate model, the firing pattern model, and the ensemble model are proposed to explain the mechanisms of LID. The “firing rate model” proposes that decreasing the mean firing rates of the output nuclei of basal ganglia (BG) including the globus pallidus internal segment and substantia nigra reticulata, along the BG pathways, induces dyskinesia. The “firing pattern model” claimed that abnormal firing pattern of a single unit activity and local field potentials may disturb the information processing in the BG, resulting in dyskinesia. The “ensemble model” described that dyskinesia symptoms might represent a distributed impairment involving many brain regions, but the number of activated neurons in the striatum correlated most strongly with dyskinesia severity. Extensive evidence for circuit mechanisms in driving LID symptoms has also been presented. LID is a multisystem disease that affects wide areas of the brain. Brain regions including the striatum, the pallidal–subthalamic network, the motor cortex, the thalamus, and the cerebellum are all involved in the pathophysiology of LID. In addition, although both amantadine and deep brain stimulation help reduce LID, these approaches have complications that limit their wide use, and a novel antidyskinetic drug is strongly needed; these require us to understand the circuit mechanism of LID more deeply.
Highlights
L-DOPA is the criterion standard of treatment for Parkinson disease
Younger age at disease onset is more likely to develop L-DOPA– induced dyskinesia (LID) (Kostic et al, 1991; Sharma et al, 2010). These risk factors seem insufficient to explain the incidence of dyskinesia in Parkinson disease (PD) patients; there is some evidence indicating that genetic factors may contribute to the occurrence of dyskinesia
In another study, baseline bursting firing pattern is increased in Parkinsonian rats, acute application of L-DOPA reduces the number of bursting neurons in the substantia nigra reticulata (SNr) of dyskinetic rats (Aristieta et al, 2016)
Summary
There are two major populations of cells in the striatum, dSPNs and iSPNs, based on their different projection targets. In PD, the deficiency of DA in the striatum causes the overactivation of indirect pathway, as well as the hypoactivation of direct pathway, resulting in the suppression of the thalamus and the cortex, which inhibits the movement. In PD, the deficiency of DA in the striatum causes the overactivation of indirect pathway, as well as the hypoactivation of direct pathway, resulting in the suppression of the thalamus and the cortex, which inhibits the movement (Figure 1; McGregor and Nelson, 2019). While in LID the DA concentration in the striatum is increased, which enhances the output of direct pathway by the stimulation of D1 receptor, the indirect pathway is inhibited via the activation of D2 receptor.
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