An Autoradiographic Study on the Pathogenesis of Levodopa-Induced Dyskinesia: Regulation of Dopamine Transporter by Levodopa in a Rat Model of Parkinson’s Disease

Abstract

Background: The development of abnormal involuntary movements or dyskinesia is a serious complication of L-3,4-dihydroxyphenylalanine (L-DOPA) therapy for Parkinson’s disease (PD). Objective: To evaluate the correlation between dopamine transporter (DAT) regulated by L-DOPA and the pathogenesis of dyskinesia in PD rats. Methods: Thirty rats were used to establish the PD model by injecting 6-hydroxydopamine into the right medial forebrain bundle. The sham surgery rats (n = 4) received 4 µl of physiological saline. Then, 19 rats in which PD has been successfully induced were randomly assigned to the L-DOPA (20 mg/kg/day; n = 15) or model (saline; n = 4) group. After 4 weeks of treatment, ¹³¹I-N-(3-fluoropropyl)-2β-carbomethoxy-3 β-(4-iodophenyl)nortropane was injected into the rats, and images of DAT in the brain were acquired using a storage phosphor plate. The levels of DAT-specific radioactivity uptake in the bilateral corpora striata (left/right) were compared. Results: There was no difference in DAT-specific radioactivity uptake between the bilateral corpora striata in the sham surgery rats. The images were clear and symmetrically distributed in the corpora striata. In PD model rats, the DAT-specific radioactivity uptake decreased on the lesioned side and the ratios of uptake between the corpora striata were increased. Accumulation of the radioligand on the lesioned side was sparse. In the L-DOPA group, the average ratio values were significantly increased in dyskinetic rats and reduced in nondyskinetic rats. In addition, the differences between the bilateral corpora striata were reduced in nondyskinetic rats. Conclusion: L-DOPA was shown to downregulate DAT in some PD model rats. That process may be involved in the pathogenesis of dyskinesia.