Targeting the D1-N-methyl-d-aspartate receptor complex reduces l-dopa-induced dyskinesia in 6-hydroxydopamine-lesioned Parkinson’s rats

Abstract

L-3,4-dihydroxyphenylalanine (l-dopa) remains the most effective therapy for Parkinson’s disease (PD), but its long-term administration is associated with the development of debilitating motor complications known as l-dopa-induced dyskinesia (LID). Enhanced function of dopamine D1 receptor (D1R) and N-methyl-d-aspartate receptor (NMDAR) is believed to participate in the pathogenesis of LID. Given the existence of physical and functional interactions between D1R and NMDAR, we explored the effects of uncoupling D1R and NMDA GluN1 (GluN1) interaction on LID by using the Tat-conjugated interfering peptide (Tat-D1-t2). In this study, we demonstrated in 6-hydroxydopamine (6-OHDA)-lesioned PD rat model that intrastriatal injection of Tat-D1-t2 alleviated dyskinetic behaviors and downregulated the phosphorylation of DARPP-32 at Thr34 induced by levodopa. Moreover, we also showed intrastriatal administration of Tat-D1-t2 elicited alterations in membranous GluN1 and D1R expression. These findings indicate that D1R/GluN1 complexes may be a molecular target with therapeutic potential for the treatment of dyskinesia in Parkinson’s patients.

Keywords:

• 6-hydroxydopamine
• Parkinson’s disease
• dyskinesia
• l-dopa
• D1 receptor
• NMDA
• protein
• protein interaction

Acknowledgments

The study was supported by the Projects of National Science Foundation of China (Nos 81171203, 81171204, 81200871, 81400925, and 81471148).

Disclosure

The authors report no conflicts of interest in this work.