Indirect Striatal Projection Neurons Drive a D2 Receptor-Dependent Pathway to Dyskinesia and Dystonia

L-DOPA-induced dyskinesia is attributed to opposite activity changes mediated by D1 and D2 dopamine receptors in the two striatal output pathways. Whereas the causal role of direct-pathway D1 receptors is well established, the specific involvement of indirect-pathway D2 receptors in dopaminergic dyskinesias has remained elusive.

We used conditional knockout approaches in mice to determine whether indirect-pathway D2 receptors causally contribute to dyskinetic and dystonic responses to dopaminergic agents.

Studies were conducted in mice with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway receiving subchronic treatments with L-DOPA or D2/D1-selective agonists. A conditional knockout of indirect-pathway D2 receptors was produced either through the entire striatum (double-transgenic Adora2a-Cre/Drd2^loxP/loxP mice) or selectively in the dopamine-denervated dorsal striatum (proenkephalin promoter-driven Cre vector delivery to Drd2^loxP/loxP mice).

The severity of L-DOPA-induced abnormal involuntary movements and dystonia was halved in both knockout models compared with control mice, whereas the treatment effect on normal motor behaviors was either not reduced or improved. All dyskinetic and dystonic features induced by the D2-selective receptor agonist sumanirole were completely abolished, whereas those induced by the D1-class agonist SKF38393 were largely unaffected. Using phosphorylated ribosomal protein S6 as an activity marker, we detected a treatment-induced recruitment of prototypical parvalbumin-positive neurons in the external globus pallidus (a target of indirect-pathway projections). This effect was inhibited in both knockout models.

We provide experimental evidence that indirect-pathway D2 receptors significantly contribute to the expression of dyskinesia during L-DOPA treatment and mediate D2 agonist-dependent dystonic features. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.