Levodopa (L-dopa) remains the most effective drug treatment for the symptomatic relief of Parkinson's disease. Unfortunately, the therapeutic effects are diminished with chronic use, as levodopa-induced dyskinesias (adverse involuntary movements) appear after intermittent, but not continuous treatment. In a rodent model of Parkinson's disease, this project will examine the mechanisms underlying behavioral sensitization during chronic continuous versus intermittent L-dopa administration at 2 dosages, 8 mg/kg/day and 100 mg/kg/day. Behavioral analyses, based on pre-clinical models of levodopa-induced sensitization, will assess motor activity. Specific basal ganglia nuclei and their target structures will undergo post-mortem analysis to determine GABAergic and metabolic activity utilizing in situ hybridization histochemistry to reveal levels of mRNA encoding for glutamate decarboxylase and cytochrome oxidase, and in vitro ligand binding to reveal binding levels/affinity to GABAa and GABAb receptors. This investigation will conclude by comparing basal ganglia organization and GABAergic activity of basal ganglia output structures to motor behavior. These results will have important implications for understanding the origin of levodopa-induced dyskinesia and therapeutic approaches to treat Parkinson's disease.
| Nielsen, Kirsten M; Soghomonian, Jean-Jacques (2003) Dual effects of intermittent or continuous L-DOPA administration on gene expression in the globus pallidus and subthalamic nucleus of adult rats with a unilateral 6-OHDA lesion. Synapse 49:246-60 |
