24-07-08(0:14:35)
Authors:
Herrmann J 1,2, Timmer M 3, Lundblad M 4, Cenci A 4, Nikkhah G 3, Winkler C 2
Institutions:
1. Department of Neurology, Hannover Medical School, Hannover, Germany
2. Department of Neurology, University of Freiburg, Freiburg, Germany
3. Department of Stereotaxic Neurosurgery, University of Freiburg, Freiburg, Germany
4. Department of Experimental Medical Science, University of Lund, Lund, Sweden
Title of abstract : L-DOPA-induced dyskinesia after uni- and bilateral dopamine-denervating lesions in the rat Parkinson model
Abstract text:
Long-term L-DOPA treatment can induce severe dyskinesia in patients with Parkinson’s disease (PD). In the rat PD model, repeated pulsatile administration of L-DOPA progressively induces involuntary movements, which resemble L-DOPA-induced dyskinesia in patients with PD. However, dyskinesia studies in the rat PD model are usually performed in animals with unilateral dopamine-denervating lesions, i.e. animals show involuntary movements only on one side of the body. We have therefore performed a study in rats with bilateral dopamine-denervating lesions. Animals received unilateral or bilateral lesions of the nigrostriatal dopaminergic projections by intrastriatal injection of 6-hydroxydopamine. The severity of the dopamine-denervating lesion was characterized in a forelimb akinesia test (cylinder test). Animals then received daily injections of L-DOPA (6mg/kg) and benserazide (15mg/kg) for 4 weeks. L-DOPA-induced involuntary movements were characterized according to a rat dyskinesia scale, which was adopted from the clinical setting. Immunohistochemical analysis included staining for tyrosine hydroxylase and FosB. Intrastriatal injections of 6-hydroxydopamine induced 70-95% reductions of nigral dopamine cells and striatal dopaminergic fiber density. Animals with unilateral lesions developed involuntary movements involving orolingual, limb and trunk muscles contralateral to the lesion. Most animals with bilateral lesions showed dyskinesia on both sides of the body. Overall dyskinesia scores in animals with bilateral lesions were 3x higher as compared to animals with unilateral lesions. Further analysis showed that dyskinesia on one side of the body was more frequent and more severe when – in addition to the lesion contralateral to the presentation of dyskinesia – there was a second dopamine-denervating lesion on the ipsilateral side. We conclude, that L-DOPA-treatment in rats with bilateral dopamine-denervating lesions induces bilateral dyskinesia, which resembles L-DOPA-induced dyskinesia in patients with PD. Furthermore, our results suggest that there is an interhemispheric functional coupling of the two nigrostriatal pathways with regard to the frequency and severity of dyskinesia.
