Molecular pathophysiology of L-DOPA-induced dyskinesia

The dopamine precursor, L-DOPA is very effective in improving the signs and symptoms of Parkinson's Disease, but has a high potential to prime the brain for the development of motor fluctuations and dyskinesia (abnormal involuntary movements). This priming process is believed to depend on maladaptive changes in gene and protein expression within the basal ganglia, and there is general agreement that an abnormal potentiation of dopamine- and glutamate-dependent signalling in striatal neurons plays a key role. We have used gene chip array technology in order to define the molecular fingerprint of L-DOPA-induced dyskinesia in a well-characterized animal model of Parkinson's disease. 6-hydroxydopamine (6-OHDA) lesioned rats were treated with L-DOPA or physiological saline for 22 days, during which a battery of behavioural tests allowed for an allocation of the animals to three groups: (i) dyskinetic rats (i.e. animals that developed abnormal involuntary movements during the course of L-DOPA treatment); (ii) rats that showed an antiakinetic response to L-DOPA without any sign of dyskinesia; (iii) non drug-treated (akinetic) controls. Total mRNA was extracted from the 6-OHDA-lesioned striata for hybridization on gene chip arrays containing over 8000 genes. Our results show that the pattern of striatal gene expression induced by chronic L-DOPA treatment is conditioned by the absence or the presence of a dyskinetic motor response. Dyskinetic rats showed a consistent upregulation of transcripts involved in Ca²⁺ homeostasis, Ca²⁺ -dependent signalling, and structural and synaptic plasticity. An upregulated expression of glutamate and GABA transporters, metabotropic glutamate receptors. and GABA-A receptor subunits was suggestive of increased GABA and glutamate transmission within the “dyskinetic“ striatum. The data also pointed toward increased oxidative stress and decreased defense mechanisms. In conclusion, this study reveals some unexpected clues to the dyskinetic action of L-DOPA and provides new directions for future pathophysiological investigation.