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Levodopa-induced dyskinesia (LID) is a major complication of long-term dopamine replacement therapy for Parkinson's disease, and becomes increasingly problematic in the advanced stage of the disease. Although the cause of LID still remains unclear, there is accumulating evidence from animal experiments that it results from maladaptive plasticity, resulting in supersensitive excitatory transmission at corticostriatal synapses. Recent work using transcranial magnetic stimulation suggests that the motor cortex displays the same supersensitivity in Parkinson's disease patients with LID. To date, the cellular mechanisms underlying the abnormal cortical plasticity have not been examined. The morphology of the dendritic spines has a strong relationship to synaptic plasticity. Therefore, we explored the spine morphology of pyramidal neurons in the motor cortex in a rat model of LID. We used control rats, 6-hydroxydopamine-lesioned rats (a model of Parkinson's disease), 6-hydroxydopamine-lesioned rats chronically treated with levodopa (a model of LID), and control rats chronically treated with levodopa. Because the direct pathway of the basal ganglia plays a central role in the development of LID, we quantified the density and size of dendritic spines in intratelencephalic (IT)-type pyramidal neurons in M1 cortex that project to the striatal medium spiny neurons in the direct pathway. The spine density was not different among the four groups. In contrast, spine size became enlarged in the Parkinson's disease and LID rat models. The enlargement was significantly greater in the LID model than in the Parkinson's disease model. This enlargement of the spines suggests that IT-type pyramidal neurons acquire supersensitivity to excitatory stimuli. To confirm this possibility, we monitored miniature excitatory postsynaptic currents (mEPSCs) in the IT-type pyramidal neurons in M1 cortex using whole-cell patch clamp. The amplitude of the mEPSCs was significantly increased in the LID model compared with the control. This indicates that the IT-type pyramidal neurons become hyperexcited in the LID model, paralleling the enlargement of spines. Thus, spine enlargement and the resultant hyperexcitability of IT-type pyramidal neurons in M1 cortex might contribute to the abnormal cortical neuronal plasticity in LID., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Maladaptive plasticity at corticostriatal synapses plays an important role in the development of levodopa-induced dyskinesia. Recently, it has been shown that synaptic plasticity is closely linked to morphologic changes of dendritic spines. To evaluate morphologic changes of dendritic spines of two types of striatal medium spiny neurons, which project to the internal segment of globus pallidus or the external segment of globus pallidus, in the levodopa-induced dyskinesia model, we used 6-hydroxydopamine-lesioned rats chronically treated with levodopa. Dendritic spines were decreased and became enlarged in the direct pathway neurons of the model of levodopa-induced dyskinesia. The same levodopa treatment to normal rats, in which no dyskinesia was observed, also induced enlargement of dendritic spines, but not a decrease in density of spines in the direct pathway neurons. These results suggest that a loss and enlargement of dendritic spines in the direct pathway neurons plays important roles in the development of levodopa-induced dyskinesia., (© 2014 International Parkinson and Movement Disorder Society.)

The aim of our present study was to determine whether exogenous L-DOPA-derived extracellular dopamine (DA) in the denervated striatum is taken up via serotonin (5-HT) transporters. Rats with dopaminergic denervation by 6-hydroxydopamine were injected with L-DOPA 50 mg/kg (i.p.) and extracellular DA levels in the denervated striatum were measured using in vivo microdialysis technique. During the experiments, fluoxetine, a selective serotonin reuptake inhibitor, was locally perfused into the striatum through the microdialysis probe. Cumulative amounts of L-DOPA-derived extracellular DA during 300 min were increased by fluoxetine dose-dependently (10 microM and 50 microM). These results suggest that reuptake of DA via 5-HT transporters plays an important role in the clearance of L-DOPA-derived DA from the extracellular space when dopaminergic neurons are extensively denervated.

Marked fluctuation of dopamine concentration in the striatum following long-term L-DOPA administration contributes to the development of L-DOPA-induced motor complications including L-DOPA-induced dyskinesias and wearing-off in patients with Parkinson's disease. We have shown that pretreatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A (5-hydroxytryptamine) receptor agonist, alleviates fluctuation of dopamine levels in the dopamine-denervated striatum of 6-hydroxydopamine-lesioned (hemiparkinsonian) rats after L-DOPA treatment. To determine whether co-administration of 8-OH-DPAT with L-DOPA prevents L-DOPA-induced motor complications, we examined rotation behavior and levels of messenger RNAs coding for dynorphin and glutamic acid decarboxylase in the striatum of 6-hydroxydopamine-lesioned rats treated with L-DOPA alone or L-DOPA + 8-OH-DPAT, twice daily, for 2 weeks. Co-administration of 8-OH-DPAT inhibited an increase of rotation behavior to L-DOPA and L-DOPA-induced increases in levels of messenger RNAs coding for dynorphin and glutamic acid decarboxylase in the dopamine-denervated striatum, both of which are established indices of L-DOPA-induced motor complications. These results suggest that pharmaceutical products that stimulate 5-HT1A receptors could prove useful in prevention of the development of L-DOPA-induced motor complications in patients with Parkinson's disease.

The medial globus pallidus plays a crucial role in generation of L-DOPA-induced dyskinesia in patients with Parkinson's disease. The 6-hydroxydopamine-lesioned rat exhibiting behavioral sensitization to L-DOPA is one useful animal model for examining L-DOPA-induced dyskinesia. To determine neuropathological abnormality responsible for behavioral sensitization, the medial globus pallidus and the substantia nigra reticulata in 6-hydroxydopamine-lesioned rats treated with L-DOPA were examined. Intermittent L-DOPA treatment induced hypertrophy of the lesioned-side of medial globus pallidus and substantia nigra reticulata of 6-hydroxydopamine-lesioned rats with behavioral sensitization to L-DOPA. Additionally, coadministration of a 5-HT1A receptor agonist, 8-hydroxy-2(di-n-propylamino)tetralin with L-DOPA, alleviated the hypertrophy with improvement of the behavioral sensitization. These results suggest that hypertrophy of the medial globus pallidus and substantia nigra reticulata is associated with induction of behavioral sensitization to L-DOPA in 6-hydroxydopamine-lesioned rats. Therefore, neuropathological changes corresponding to hypertrophy might underlie L-DOPA-induced dyskinesia in patients with Parkinson's disease.

To determine whether the adenosine A2A receptor might play a role in L-DOPA-induced dyskinesia in Parkinson's disease, we analyzed changes in the expression of A2A receptor mRNA in response to intermittent treatment with L-DOPA in rats with dopaminergic denervation by 6-hydroxydopamine (OHDA) infusion into the medial forebrain bundle. Intermittent treatment with L-DOPA increased A2A receptor mRNA levels in the dopamine-depleted striatum of 6-OHDA-lesioned rats exhibiting behavioral sensitization to L-DOPA. These results suggest that A2A receptor activation is associated with the development of motor complications induced by L-DOPA treatment., (Copyright 2004 Wiley-Liss, Inc.)

A rapid and excessive increase in extracellular dopamine(DA) after L-DOPA administration is considered one of the major causes for L-DOPA-induced peak-dose dyskinesia. Therefore, inhibition of excessive rise in L-DOPA-derived DA is likely to be an ideal treatment for L-DOPA-induced dyskinesia. Based on our previous experimental studies that 8-OH-DPAT, a potent 5-HT1A agonist, attenuates an increase in L-DOPA-induced extracellular DA in the striatum of the rat model of Parkinson's disease, we hypothesized that L-DOPA-induced dyskinesia in patients with Parkinson's disease is alleviated by a 5-HT1A agonist. In the present study, we administered tandospirone citrate, a selective 5-HT1A agonist, to patients with Parkinson's disease suffering from L-DOPA-induced dyskinesia. Tandospirone(15-60 mg/day) was administered to 10 patients with L-DOPA-induced peak-dose dyskinesia. Twelve weeks after tandospirone treatment, duration of dyskinesia, subjective and objective severity of dyskinesia, and parkinsonian features were evaluated. Severity of dyskinesia was decreased in 5 patients; among these, 3 patients experienced slight worsening of parkinsonian features. Four patients showed no change in dyskinesia; among these, 2 patients showed worsening of parkinsonian features. One patient had slight worsening of dyskinesia without any change in parkinsonian features. The present study demonstrated that tandospirone is effective in alleviating L-DOPA-induced dyskinesia in 50% of the patients. However, at the same time 50% patients showed slight worsening of parkinsonian features. Both the anti-dyskinetic effect and the worsening of parkinsonian features are thought to be induced by tandospirone's potent 5-HT1A agonistic activity. Diverse effect of tandospirone may be caused by its partial agonist activity on 5-HT1A receptors, or may indicate that other causes for the expression of dyskinesia exist apart from excessive rise in brain DA levels. Administration of a 5-HT1A agonist is a choice for patients with dyskinesia if the care is taken so as not to induce worsening of parkinsonian features. Further studies such as double-blind trials are needed to confirm the usefulness of a 5-HT1A agonist for L-DOPA-induced dyskinesia.

Levodopa-induced dyskinesia has been suggested to result from maladaptive plasticity at corticostriatal synapses. Synaptic plasticity is based upon morphologic changes of dendritic spines. To elucidate whether the morphologic changes of spines occur in the striatum of rat models of levodopa-induced dyskinesia, we examined immunoreactivity of drebrin, an actin-binding protein localized in dendritic spines of excitatory synapses, using 6-hydroxydopamine-lesioned rats repeatedly treated with levodopa. The cross-sectional area of drebrin-immunoreactive organelles, putative spines, in the dopamine-denervated striatum of the levodopa-induced dyskinesia model was greater than that of the Parkinson's disease model. Immunoelectron microscopic examinations confirmed that drebrin-immunoreactive spines became enlarged in the dopamine-denervated striatum of the levodopa-induced dyskinesia model, but not in the Parkinson's disease model. These results suggest that the development of levodopa-induced dyskinesia is associated with enlargement of dendritic spines at corticostriatal excitatory synapses. [ABSTRACT FROM AUTHOR]