Comparative effects of acute or chronic administration of levodopa to 6-hydroxydopamine-lesioned rats on the expression of glutamic acid decarboxylase in the neostriatum and GABAA receptors subunits in the substantia nigra, pars reticulata

Current evidence suggests that behavioral sensitization to the chronic administration of levodopa (l-DOPA) to dopamine-depleted animals involves a plasticity of GABA-mediated signaling in output regions of the basal ganglia. The purpose of this study was to compare in adult rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion the effects of an acute or chronic (for 3 or 7 days) injection of l-DOPA on mRNA levels encoding for glutamic acid decarboxylase (GAD65 and GAD67) in the striatum and GABAA receptor α1, β2 and γ2 subunits in the substantia nigra, pars reticulata (SNr), by in situ hybridization histochemistry. In addition, immunostaining levels for the α1 subunit were examined in the SNr. In agreement with previous studies, we found that l-DOPA administration increased GAD mRNA levels in the striatum of 6-OHDA-lesioned rats. However, the magnitude of this effect increased with the number of injections of l-DOPA. On the other hand, we found that 6-OHDA lesions resulted in increases in α1, β2 and γ2 mRNA levels in the ipsilateral SNr, which were normalized or decreased compared with the contralateral side by the acute or chronic administration of l-DOPA. In addition, α1 immunostaining in the SNr was significantly decreased in rats injected for 7 days but not for 3 days or acutely with l-DOPA. Our results demonstrate that a chronic administration of l-DOPA results in a progressive increase in GAD and decrease in GABAA receptor expression in the striatum and SNr, respectively. They provide further evidence that behavioral sensitization and dyskinesia induced by a chronic administration of l-DOPA in an experimental model of Parkinson's disease is paralleled by a plasticity of GABA-mediated signaling in the SNr.