{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T09:57:40Z","timestamp":1788343060948,"version":"build-2803163510"},"reference-count":51,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2020\u201002696"],"award-info":[{"award-number":["2020\u201002696"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2024\u201002491"],"award-info":[{"award-number":["2024\u201002491"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"publisher","award":["R336\u20102020\u20101035"],"award-info":[{"award-number":["R336\u20102020\u20101035"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>L\u2010DOPA\u2010induced 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\u2010pathway D1 receptors is well established, the specific involvement of indirect\u2010pathway D2 receptors in dopaminergic dyskinesias has remained elusive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We used conditional knockout approaches in mice to determine whether indirect\u2010pathway D2 receptors causally contribute to dyskinetic and dystonic responses to dopaminergic agents.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Studies were conducted in mice with unilateral 6\u2010hydroxydopamine lesions of the nigrostriatal pathway receiving subchronic treatments with L\u2010DOPA or D2\/D1\u2010selective agonists. A conditional knockout of indirect\u2010pathway D2 receptors was produced either through the entire striatum (double\u2010transgenic\n                      <jats:italic>Adora2a<\/jats:italic>\n                      \u2010Cre\/\n                      <jats:italic>Drd2<\/jats:italic>\n                      <jats:sup>loxP\/loxP<\/jats:sup>\n                      mice) or selectively in the dopamine\u2010denervated dorsal striatum (proenkephalin promoter\u2010driven Cre vector delivery to\n                      <jats:italic>Drd2<\/jats:italic>\n                      <jats:sup>loxP\/loxP<\/jats:sup>\n                      mice).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The severity of L\u2010DOPA\u2010induced 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\u2010selective receptor agonist sumanirole were completely abolished, whereas those induced by the D1\u2010class agonist SKF38393 were largely unaffected. Using phosphorylated ribosomal protein S6 as an activity marker, we detected a treatment\u2010induced recruitment of prototypical parvalbumin\u2010positive neurons in the external globus pallidus (a target of indirect\u2010pathway projections). This effect was inhibited in both knockout models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      We provide experimental evidence that indirect\u2010pathway D2 receptors significantly contribute to the expression of dyskinesia during L\u2010DOPA treatment and mediate D2 agonist\u2010dependent dystonic features. \u00a9 2026 The Author(s).\n                      <jats:italic>Movement Disorders<\/jats:italic>\n                      published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.\n                    <\/jats:p>\n                  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