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Dyskinesia is a major side effect of chronic levodopa (L-DOPA) administration, the reference treatment for Parkinson's disease (PD). High-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates parkinsonian motor symptoms and indirectly improves dyskinesia by decreasing L-DOPA requirement. However, inadequate stimulation can also trigger dyskinetic movements in PD patients and animal models. Here, we investigated the possible association between L-DOPA- and STN-HFS-induced dyskinesia and regulation of the NR2B subunit of NMDA receptors in the rodent model of PD. We subjected 6-OHDA-lesioned rats to HFS for 1h, at an intensity triggering forelimb dyskinesia. Other 6-OHDA-lesioned rats were treated with chronic high doses of L-DOPA for ten days, to induce abnormal involuntary movements. The 6-OHDA lesion regulated NR2B only in the SNr, where the activation of NR2B was observed (as assessed by phosphorylation of the Tyr1472 residue). Both STN-HFS and L-DOPA dyskinesiogenic treatments induced NR2B activation in the STN and EP, but only L-DOPA triggered NR2B hyperphosphorylation in the striatum. Finally, the use of CP-101,606 exacerbated L-DOPA-induced motor behavior and associated NR2B hyperphosphorylation in the striatum, STN and EP. Thus, NR2B activation in basal ganglia structures is correlated with dyskinesia., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The cardinal symptoms of Parkinson's disease (PD), akinesia, rigidity and tremor, are only observed when the striatal level of dopamine (DA) is decreased by 60-80%. It is likely that compensatory mechanisms during the early phase of DA depletion delay the appearance of motor symptoms. In a previous study, we proposed a new PD monkey model with progressive MPTP intoxication. Monkeys developed all of the motor symptoms and then fully recovered despite a large DA cell loss in the substantia nigra (SN). Compensatory mechanisms certainly help to offset the dysfunction induced by the DA lesion, facilitating motor recovery in this model. Neurotransmitter measurements in the striatal sensorimotor and associative/limbic territories of these monkeys subsequently revealed that DA and serotonin (5-HT) could play a role in recovery mechanisms. To try to determine the involvement of these neurotransmitters in compensatory mechanisms, we performed local injections of DA and 5-HT antagonists (cis-flupenthixol and mianserin, respectively) into these two striatal territories and into the external segment of the globus pallidus (GPe). Injections were performed on monkeys that were in an asymptomatic state after motor recovery. Most parkinsonian motor symptoms reappeared in animals with DA antagonist injections either in sensorimotor, associative/limbic striatal territories or in the GPe. In contrast to the effects with DA antagonist, there were mild parkinsonian effects with 5-HT antagonist, especially after injections in sensorimotor territories of the striatum and the GPe. These results support a possible, but slight, involvement of 5-HT in compensatory mechanisms and highlight the possible participation of 5-HT in some behavioural disorders. Furthermore, these results support the notion that the residual DA in the different striatal territories and the GPe could be involved in important mechanisms of compensation in PD., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We compared for the first time the effects of de novo versus long-term l-Dopa treatment inducing abnormal involuntary movement on striatal gene profiles and related bio-associations in the 6-hydroxydopamine rat model of Parkinson's disease. We examined the pattern of striatal messenger RNA expression over 4854 genes in hemiparkinsonian rats treated acutely or chronically with l-Dopa, and subsequently verified some of the gene alterations by in situ hybridization or real-time quantitative PCR. We found that de novo and long-term l-Dopa share common gene regulation features involving phosphorylation, signal transduction, secretion, transcription, translation, homeostasis, exocytosis and synaptic transmission processes. We also found that the transcriptomic response is enhanced by long-term l-Dopa and that specific biological alterations are underlying abnormal motor behavior. Processes such as growth, synaptogenesis, neurogenesis and cell proliferation may be particularly relevant to the long-term action of l-Dopa.