Subregion-specific suppression of dopamine D1 receptor expression prevents L-DOPA-induced dyskinesia in a mouse model of Parkinson's disease

Abstract

L-DOPA-induced dyskinesia (LID) is a debilitating motor complication that develops following prolonged L-DOPA therapy in patients with Parkinson's disease (PD). Aberrant activation of dopamine D1 receptor (DRD1) signaling in D1-type/direct pathway medium spiny neurons (MSNs) of the striatum plays a critical role in the pathophysiology of LID. We previously characterized DRD1 signaling in seven striatal subregions and found that upregulation of DRD1 signaling in the intermediate/caudal part (IC) is associated with LID in a mouse model of PD. Here, we investigated whether DRD1 expression in the IC plays a causal role in LID development. Using an adeno-associated virus (AAV) expressing a short hairpin RNA against Drd1 (AAV-shDrd1), we selectively knocked down DRD1 expression in the IC of male mice. In unilateral 6-hydroxydopamine-lesioned mice, DRD1 knockdown in the IC significantly attenuated LID after acute and chronic L-DOPA treatment. In contrast, knockdown in either the rostral or intermediate/rostral part, previously identified as the LID-unrelated subregion, did not affect LID. These findings highlight the essential role of DRD1 and its signaling in the IC in LID development, providing valuable insights for developing novel therapeutic approaches. © 2025 Elsevier B.V.