{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:13:57Z","timestamp":1772118837522,"version":"3.50.1"},"reference-count":43,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,1,24]],"date-time":"2019-01-24T00:00:00Z","timestamp":1548288000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes for Health Research","doi-asserted-by":"crossref","award":["MOP-81321"],"award-info":[{"award-number":["MOP-81321"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes for Health Research","doi-asserted-by":"crossref","award":["MOP-130407"],"award-info":[{"award-number":["MOP-130407"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Fonds de Recherche du Qu\u00e9bec en Sant\u00e9"},{"name":"CNS research group (GRSNC) of the University of Montreal"}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2019,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tardive dyskinesia is a delayed and potentially irreversible motor complication arising from chronic exposure to antipsychotic drugs. Interaction of antipsychotic drugs with G protein\u2010coupled receptors triggers multiple intracellular events. Nevertheless, signaling pathways that might be associated with chronic unwanted effects of antipsychotic drugs remain elusive. In this study, we aimed to better understand kinase signaling associated with the expression of tardive dyskinesia in nonhuman primates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We exposed capuchin monkeys to prolonged haloperidol (n = 10) or clozapine (n = 6) treatments. Untreated animals were used as controls (n = 6). Half of haloperidol\u2010treated animals (5) developed mild tardive dyskinesia similar to that found in humans. Using Western blots and immunochemistry, we measured putamen total and phosphorylated protein kinase levels associated with canonical and noncanonical signaling cascades of G protein\u2010coupled receptors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Antipsychotic drugs enhanced pDARPP\u201032 and pERK1\/2, but no difference ws observed in phosphoprotein kinase levels between dyskinetic and nondyskinetic monkeys. On the other hand, comparison of kinase levels between haloperidol\u2010treated dyskinetic and nondyskinetic monkeys indicated that dyskinetic animals had lower GRK6 and \u03b2\u2010arrestin2 levels. Levels of pAkt and pGSK\u20103\u03b2 were also reduced, but only haloperidol\u2010treated monkeys that developed tardive dyskinesia had reduced pGSK\u20103\u03b2 levels, whereas pAkt levels in dyskinetic animals positively correlated with dyskinetic scores. Interestingly, double immunofluorescence labeling showed that putamen dopamine D3 receptor levels were upregulated and that D3\/pAkt colocalization was enriched in haloperidol\u2010treated animals displaying tardive dyskinesia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our results suggest that upregulation of putamen dopamine D3 receptor and alterations along the noncanonical GRK6\/\u03b2\u2010arrestin2\/Akt\/GSK\u20103\u03b2 molecular cascade are associated with the development of tardive dyskinesia in nonhuman primates. \u00a9 2019 International Parkinson and Movement Disorder Society<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mds.27630","type":"journal-article","created":{"date-parts":[[2019,1,24]],"date-time":"2019-01-24T15:59:36Z","timestamp":1548345576000},"page":"717-726","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Tardive dyskinesia is associated with altered putamen Akt\/GSK\u20103\u03b2 signaling in nonhuman primates"],"prefix":"10.1002","volume":"34","author":[{"given":"Giovanni","family":"Hernandez","sequence":"first","affiliation":[{"name":"Facult\u00e9 de Pharmacie Universit\u00e9 de Montr\u00e9al  Montr\u00e9al Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Souha","family":"Mahmoudi","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de Pharmacie Universit\u00e9 de Montr\u00e9al  Montr\u00e9al Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michel","family":"Cyr","sequence":"additional","affiliation":[{"name":"Groupe 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