Levodopa induces a cytoplasmic localization of D1 dopamine receptors in striatal neurons in Parkinson's disease

Parkinson's disease is characterized by a massive loss of nigral dopamine neurons that results in a reduction of dopamine concentrations in the striatum. The most commonly used treatment for this disease is levodopa therapy to restore striatal dopamine. This treatment is mediated by dopamine receptors, but the effect of treatment and the disease on receptor distribution is unknown. In this study, the distribution of D1 dopamine receptors was analyzed at the cellular and subcellular level in the striatum of 5 patients with Parkinson's disease (all treated with levodopa) and 4 control subjects. In the control brains, D1 dopamine receptors were mostly detected on the plasma membrane of medium-sized spiny neurons. The quantitative analysis performed at the ultrastructural level in patients with Parkinson's disease revealed an increase in immunostaining in the cytoplasm of medium-sized neurons. This effect was likely the result of the treatment rather than the dopaminergic denervation, as such changes were not observed in the striatum of rats with a unilateral 6-hydroxydopamine nigrostriatal lesion, but were present in normal or lesioned rats treated with a D1 dopamine agonist. Altered localization of D1 dopamine receptors may participate in the occurrence of side effects of levodopa therapy such as dyskinesia and fluctuations in motor performances.