Contribution of D1 receptor stimulation to the development of levodopa-induced dyskinesias in 6-hydroxydopamine-lesioned rats

Abstract

Dyskinesias represent a troublesome complication of l-DOPA therapy in Parkinson's disease patients. However, the pathogenesis of l-DOPA-induced dyskinesia (LID) remains to be determined. The clinical fact that pallidotomy has a striking anti-dyskinesic effect provides evidence that the medial globus pallidus (MGP) plays a crucial role in the development of LID. We have shown that intermittent l-DOPA treatment induced hypertrophy of MGP with dyskinesias in 6-hydroxydopamine (OHDA)-lesioned hemiparkinsonian rats. The hypertrophy resulted from enlargement of axon terminals of the direct pathway (GABAergic projection from the striatum to MGP). This observation implies that pallidotomy has ameliorative effects on LID, since the procedure breaks down the enlargement. Striatal neurons in the direct pathway express dopamine D 1 receptors. Taken together, our results strongly suggest that abnormal stimulation of striatal D 1 receptors by l-DOPA-derived dopamine is a primary cause of hypertrophy of MGP and probably LID. To prove the hypothesis, we examined the motor behavior and neuropathological changes in MGP of 6-OHDA-lesioned rats intermittently treated (twice daily for 14 days) with saline, SKF38393 (D 1 agonist), quinpirole (D 2 agonist) and l-DOPA (D 1 and D 2 agonist). Dyskinesia was induced markedly by SKF38393 and l-DOPA in 6-OHDA-lesioned rats, but minimally by quinpirole. Treatment with SKF38393 and l-DOPA caused hypertrophy of MGP in the lesioned side of 6-OHDA-lesioned rats, although quinpirole treatment had no effect on the MGP volume. Enlargement of axon terminals in MGP of the lesioned side was observed in 6-OHDA-lesioned rats treated with SKF38393 and l-DOPA, but such a change did not occur in 6-OHDA-lesioned rats treated with quinpirole. These results suggest that dopamine D 1 receptor stimulation is essential to induce hypertrophy of MGP and LID.