L-DOPA-induced dyskinesia in rats with partial dopamine-denervating lesions: relation to pre- and post-synaptic markers
Field:	Disorders of the nervous system
Authors:	Winkler, Christian Kirik, Deniz Björklund, Anders Cenci-Nilsson, Angela
Address of presenting author:	Dept. of Physiological Sciences Div. of Neurobiology Sölvegatan 17 22362 Lund
E-mail:	Christian.Winkler@mphy.lu.se
Phone:	046-2220527
Fax:	046-2220561
Text of abstract:	One of the main side effects of L-DOPA pharmacotherapy in Parkinsonian patients is the development of L-DOPA-induced dyskinesias. It has been proposed that the development of these abnormal involuntary movements may depend on the degeneration of the nigrostriatal system, i.e. the more the neurodegenerative process has proceeded, the more susceptible the patients are to develop dyskinesias. The aim of our study was to characterize effects of L-DOPA on different motor parameters in the rat Parkinson model. Rats with complete or partial dopamine (DA)-denervating lesions received single daily low-dose i.p. injections of L-DOPA (6 mg/kg) over a 4 week period. Antiparkinsonian effects of L-DOPA were assessed in sensorimotor tests (stepping and skilled forelimb use). The dyskinetic effects of L-DOPA were assessed using a rat dyskinesia scale that has been recently introduced in our laboratory. Rats with > 80% DA-denervating lesions, but not intact controls or rats with < 80% DA-denervating lesions, gradually developed abnormal movements, which affected cranial, trunk, or forelimb muscles on the side contralateral to the lesion. The severity and amplitude of these movements was markedly more pronounced in rats with complete (98-100%) DA-denervation. Besides, only rats with complete lesions exhibited contralateral turning in response to L-DOPA. Performance in the stepping test was improved by L-DOPA, and this improvement was not lost in dyskinetic rats. However, even mild dyskinesias disrupted the rats´ performance in the staircase test. Histochemical analyses showed an elevation of Fos B protein and prodynorphin mRNA expression in the striatum in dyskinetic animals only. The number of Fos B-positive cells and the amount of prodynorphin mRNA expression were strongly correlated with the severity of the dyskinesia. These data show that, in the rat model of Parkinson´s disease, the magnitude of DA-denervation determines the liability to L-DOPA-induced dyskinesia, while levels of striatal Fos B and prodynorphin mRNA expression can predict its severity and topographic distribution.
Keywords:	dyskinesia, Parkinson´s disease, L-DOPA, Dynorphin, Fos B

Created 2000-03-15