The systemic administration of agonists of dopamine receptors remains one of the most effective therapeutic interventions used for the symptomatic treatment of Parkinson's disease. However, the chronic administration of these agonists over several months-years can induce the gradual development of debilitating abnormal involuntary movements such as dyskinesia. Current models of the basal ganglia favor the hypothesis that the chronic administration of dopaminergic agents involves an increased/abnormal GABA signaling in the substantia nigra, pars reticulata (SNr), and in the internal pallidum. We propose to examine this hypothesis in a rodent experimental model of Parkinson's disease.
The specific aims are: 1-To test the hypothesis that the chronic administration of agonists of dopamine receptors to 6-OHDA-lesioned rats alters the expression of molecules involved in the regulation of GABA levels in neurons that provide an input to the SNr/internal pallidum; 2-To test the hypothesis that increases in basal extracellular GABA levels in the SNr/internal pallidum are involved in the effects of long-term administration of agonists. 3-To test the hypothesis that plasticity of GABA receptors in the SNr plays a role in the effects of chronic administration of dopaminergic agents. These studies will involve quantitative in situ hybridization histochemistry to measure changes in mRNA levels, microdialysis to measure changes in GABA levels and intranigral administration of pharmacological agents acting on GABA levels or GABA receptors to alter agonist-induced circling in rats unilaterally lesioned with 6-OHDA.
