Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Andreoli, Laura LU ; Nyman, Teodor LU orcid ; Espa, Elena LU orcid ; Jakobsson, Johan LU orcid ; Elabi, Osama F. LU and Cenci, Maria Angela LU orcid (2026) In Movement Disorders
Abstract

Background: 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. Objectives: We used conditional knockout approaches in mice to determine whether indirect-pathway D2 receptors causally contribute to dyskinetic and dystonic responses to dopaminergic agents. Methods: 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... (More)

Background: 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. Objectives: We used conditional knockout approaches in mice to determine whether indirect-pathway D2 receptors causally contribute to dyskinetic and dystonic responses to dopaminergic agents. Methods: 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/Drd2loxP/loxP mice) or selectively in the dopamine-denervated dorsal striatum (proenkephalin promoter-driven Cre vector delivery to Drd2loxP/loxP mice). Results: 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. Conclusions: 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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
dopamine agonists, levodopa-induced dyskinesias, Parkinson's disease, pathophysiology, rodent models
in
Movement Disorders
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:105036149110
  • pmid:42003734
ISSN
0885-3185
DOI
10.1002/mds.70299
language
English
LU publication?
yes
id
8e4a2635-1a08-48d1-a66a-fb50ae416206
date added to LUP
2026-05-25 11:25:06
date last changed
2026-05-26 03:01:15
@article{8e4a2635-1a08-48d1-a66a-fb50ae416206,
  abstract     = {{<p>Background: 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. Objectives: We used conditional knockout approaches in mice to determine whether indirect-pathway D2 receptors causally contribute to dyskinetic and dystonic responses to dopaminergic agents. Methods: 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<sup>loxP/loxP</sup> mice) or selectively in the dopamine-denervated dorsal striatum (proenkephalin promoter-driven Cre vector delivery to Drd2<sup>loxP/loxP</sup> mice). Results: 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. Conclusions: 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.</p>}},
  author       = {{Andreoli, Laura and Nyman, Teodor and Espa, Elena and Jakobsson, Johan and Elabi, Osama F. and Cenci, Maria Angela}},
  issn         = {{0885-3185}},
  keywords     = {{dopamine agonists; levodopa-induced dyskinesias; Parkinson's disease; pathophysiology; rodent models}},
  language     = {{eng}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Movement Disorders}},
  title        = {{Indirect Striatal Projection Neurons Drive a D2 Receptor-Dependent Pathway to Dyskinesia and Dystonia}},
  url          = {{http://dx.doi.org/10.1002/mds.70299}},
  doi          = {{10.1002/mds.70299}},
  year         = {{2026}},
}