{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:43:44Z","timestamp":1790739824255,"version":"4.1.0"},"reference-count":50,"publisher":"Portland Press Ltd.","issue":"2","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,4,1]]},"abstract":"<jats:p>PD (Parkinson's disease) is characterized by some typical motor features that are caused by striatal dopamine depletion and respond well to dopamine-replacement therapy with L-dopa. Unfortunately, the majority of PD patients treated with L-dopa develop abnormal involuntary movements (dyskinesias) within a few years. The mechanisms underlying the development of LIDs (L-dopa-induced dyskinesias) involve, on one hand, a presynaptic dysregulation of dopamine release and clearance and, on the other hand, an abnormal postsynaptic response to dopamine in the brain. There is a large amount of evidence that these dopamine-dependent mechanisms are modulated by glutamatergic pathways and glutamate receptors. The present article summarizes the pathophysiological role of glutamatergic pathways in LID and reviews pre-clinical and clinical results obtained using pharmacological modulators of different classes and subtypes of glutamate receptors to treat parkinsonian dyskinesias.<\/jats:p>","DOI":"10.1042\/bst20140006","type":"journal-article","created":{"date-parts":[[2014,3,20]],"date-time":"2014-03-20T12:39:45Z","timestamp":1395319185000},"page":"600-604","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Glutamatergic pathways as a target for the treatment of dyskinesias in Parkinson's disease"],"prefix":"10.1042","volume":"42","author":[{"given":"M.\u00a0Angela","family":"Cenci","sequence":"first","affiliation":[{"name":"Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, BMC F11, 221 84 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2014,3,20]]},"reference":[{"key":"2021111720521465800_B1","doi-asserted-by":"crossref","first-page":"670","DOI":"10.2174\/187152711797247885","article-title":"Current options and future possibilities for the treatment of dyskinesia and motor fluctuations in Parkinson's disease","volume":"10","author":"Cenci","year":"2011","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"2021111720521465800_B2","doi-asserted-by":"crossref","first-page":"189","DOI":"10.3233\/JPD-2012-120103","article-title":"Levodopa-induced dyskinesias: clinical features, incidence, risk factors, management and impact on quality of life","volume":"2","author":"Manson","year":"2012","journal-title":"J. Parkinson's Dis."},{"key":"2021111720521465800_B3","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.brainresbull.2004.10.013","article-title":"Dyskinesias and dopamine cell replacement in Parkinson's disease: a clinical perspective","volume":"68","author":"Hagell","year":"2005","journal-title":"Brain Res. Bull."},{"key":"2021111720521465800_B4","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.nbd.2005.11.011","article-title":"The impact of graft size on the development of dyskinesia following intrastriatal grafting of embryonic dopamine neurons in the rat","volume":"22","author":"Lane","year":"2006","journal-title":"Neurobiol. Dis."},{"key":"2021111720521465800_B5","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.tins.2007.03.005","article-title":"Dopamine dysregulation of movement control in L-DOPA-induced dyskinesia","volume":"30","author":"Cenci","year":"2007","journal-title":"Trends Neurosci."},{"key":"2021111720521465800_B6","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0079-6123(10)83011-0","article-title":"Maladaptive striatal plasticity in L-DOPA-induced dyskinesia","volume":"183","author":"Cenci","year":"2010","journal-title":"Prog. Brain Res."},{"key":"2021111720521465800_B7","doi-asserted-by":"crossref","DOI":"10.1523\/JNEUROSCI.2702-13.2014","article-title":"Mechanisms of dopamine D1 receptor-mediated ERK1\/2 activation in the parkinsonian striatum and their modulation by metabotropic glutamate receptor type\u00a05","author":"Fieblinger","year":"2014","journal-title":"J. Neurosci."},{"key":"2021111720521465800_B8","doi-asserted-by":"crossref","first-page":"21824","DOI":"10.1073\/pnas.1012071107","article-title":"Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with L-dopa-induced dyskinesia","volume":"107","author":"Fasano","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111720521465800_B9","doi-asserted-by":"crossref","first-page":"6995","DOI":"10.1523\/JNEUROSCI.0852-07.2007","article-title":"Critical involvement of cAMP\/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia","volume":"27","author":"Santini","year":"2007","journal-title":"J. Neurosci."},{"key":"2021111720521465800_B10","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1016\/j.biopsych.2006.11.032","article-title":"Spatiotemporal pattern of striatal ERK1\/2 phosphorylation in a rat model of L-DOPA-induced dyskinesia and the role of dopamine D1 receptors","volume":"62","author":"Westin","year":"2007","journal-title":"Biol. Psychiatry"},{"key":"2021111720521465800_B11","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.pneurobio.2011.10.005","article-title":"Glutamatergic mechanisms in the dyskinesias induced by pharmacological dopamine replacement and deep brain stimulation for the treatment of Parkinson's disease","volume":"96","author":"Sgambato-Faure","year":"2012","journal-title":"Prog. Neurobiol."},{"key":"2021111720521465800_B12","doi-asserted-by":"crossref","first-page":"II36","DOI":"10.1007\/PL00007759","article-title":"Antiparkinsonian and antidyskinetic activity of drugs targeting central glutamatergic mechanisms","volume":"247","author":"Chase","year":"2000","journal-title":"J. Neurol."},{"key":"2021111720521465800_B13","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1002\/mds.23829","article-title":"The Movement Disorder Society Evidence-Based Medicine Review Update: treatments for the motor symptoms of Parkinson's disease","volume":"26","author":"Fox","year":"2011","journal-title":"Mov. Disord."},{"key":"2021111720521465800_B14","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1093\/brain\/awr028","article-title":"Glutamate NMDA receptor dysregulation in Parkinson's disease with dyskinesias","volume":"134","author":"Ahmed","year":"2011","journal-title":"Brain"},{"key":"2021111720521465800_B15","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.expneurol.2011.02.012","article-title":"Local modulation of striatal glutamate efflux by serotonin 1A receptor stimulation in dyskinetic, hemiparkinsonian rats","volume":"229","author":"Dupre","year":"2011","journal-title":"Exp. Neurol."},{"key":"2021111720521465800_B16","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.nbd.2011.09.015","article-title":"In\u00a0vivo evidence for a differential contribution of striatal and nigral D1 and D2 receptors to L-DOPA induced dyskinesia and the accompanying surge of nigral amino acid levels","volume":"45","author":"Mela","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"2021111720521465800_B17","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/nn1040","article-title":"Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia","volume":"6","author":"Picconi","year":"2003","journal-title":"Nat. Neurosci."},{"key":"2021111720521465800_B18","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.nbd.2007.10.001","article-title":"L-DOPA dosage is critically involved in dyskinesia via loss of synaptic depotentiation","volume":"29","author":"Picconi","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"2021111720521465800_B19","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/nrn3504","article-title":"NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease","volume":"14","author":"Paoletti","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"2021111720521465800_B20","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0278-5846(01)00237-8","article-title":"Alteration of glutamate receptors in the striatum of dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys following dopamine agonist treatment","volume":"26","author":"Calon","year":"2002","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"2021111720521465800_B21","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.nbd.2003.07.003","article-title":"Levodopa-induced motor complications are associated with alterations of glutamate receptors in Parkinson's disease","volume":"14","author":"Calon","year":"2003","journal-title":"Neurobiol. Dis."},{"key":"2021111720521465800_B22","doi-asserted-by":"crossref","first-page":"S86","DOI":"10.1016\/S1471-1931(00)00018-5","article-title":"Striatal dopamine- and glutamate-mediated dysregulation in experimental parkinsonism","volume":"23","author":"Chase","year":"2000","journal-title":"Trends Neurosci."},{"key":"2021111720521465800_B23","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1002\/mds.22169","article-title":"Effects of a NR2B selective NMDA glutamate antagonist, CP-101,606, on dyskinesia and Parkinsonism","volume":"23","author":"Nutt","year":"2008","journal-title":"Mov. Disord."},{"key":"2021111720521465800_B24","doi-asserted-by":"crossref","first-page":"2914","DOI":"10.1523\/JNEUROSCI.5326-05.2006","article-title":"A critical interaction between NR2B and MAGUK in L-DOPA induced dyskinesia","volume":"26","author":"Gardoni","year":"2006","journal-title":"J. Neurosci."},{"key":"2021111720521465800_B25","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/0166-2236(93)90093-2","article-title":"The TINS\/TiPS Lecture: the molecular biology of mammalian glutamate receptor channels","volume":"16","author":"Seeburg","year":"1993","journal-title":"Trends Neurosci."},{"key":"2021111720521465800_B26","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.expneurol.2005.08.017","article-title":"Combined blockade of AMPA and NMDA glutamate receptors reduces levodopa-induced motor complications in animal models of PD","volume":"196","author":"Bibbiani","year":"2005","journal-title":"Exp. Neurol."},{"key":"2021111720521465800_B27","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1111\/j.1471-4159.2010.06776.x","article-title":"Calcium-permeable AMPA receptors are involved in the induction and expression of L-DOPA-induced dyskinesia in Parkinson's disease","volume":"114","author":"Kobylecki","year":"2010","journal-title":"J. Neurochem."},{"key":"2021111720521465800_B28","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1212\/WNL.54.8.1589","article-title":"AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkeys","volume":"54","author":"Konitsiotis","year":"2000","journal-title":"Neurology"},{"key":"2021111720521465800_B29","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/mds.20345","article-title":"Topiramate reduces levodopa-induced dyskinesia in the MPTP-lesioned marmoset model of Parkinson's disease","volume":"20","author":"Silverdale","year":"2005","journal-title":"Mov. Disord."},{"key":"2021111720521465800_B30","doi-asserted-by":"crossref","first-page":"2354","DOI":"10.1002\/mds.23867","article-title":"Synergistic antidyskinetic effects of topiramate and amantadine in animal models of Parkinson's disease","volume":"26","author":"Kobylecki","year":"2011","journal-title":"Mov. Disord."},{"key":"2021111720521465800_B31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0028-3908(94)00129-G","article-title":"The metabotropic glutamate receptors: structure and functions","volume":"34","author":"Pin","year":"1995","journal-title":"Neuropharmacology"},{"key":"2021111720521465800_B32","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/nrn1763","article-title":"Metabotropic glutamate receptors in the basal ganglia motor circuit","volume":"6","author":"Conn","year":"2005","journal-title":"Nat. Rev. Neurosci."},{"key":"2021111720521465800_B33","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.brainresbull.2005.12.009","article-title":"Effects of group I metabotropic glutamate receptors blockade in experimental models of Parkinson's disease","volume":"69","author":"Dekundy","year":"2006","journal-title":"Brain Res. Bull."},{"key":"2021111720521465800_B34","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1111\/j.1471-4159.2007.04456.x","article-title":"Antagonism of metabotropic glutamate receptor type\u00a05 attenuates L-DOPA-induced dyskinesia and its molecular and neurochemical correlates in a rat model of Parkinson's disease","volume":"101","author":"Mela","year":"2007","journal-title":"J. Neurochem."},{"key":"2021111720521465800_B35","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1124\/jpet.108.150425","article-title":"Pharmacological modulation of glutamate transmission in a rat model of L-DOPA-induced dyskinesia: effects on motor behavior and striatal nuclear signaling","volume":"330","author":"Rylander","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021111720521465800_B36","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1146\/annurev-physiol-021909-135843","article-title":"Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior","volume":"72","author":"Halassa","year":"2010","journal-title":"Annu. Rev. Physiol."},{"key":"2021111720521465800_B37","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.tins.2008.11.005","article-title":"Astrocytes and the regulation of cerebral blood flow","volume":"32","author":"Koehler","year":"2009","journal-title":"Trends Neurosci."},{"key":"2021111720521465800_B38","doi-asserted-by":"crossref","first-page":"4201","DOI":"10.1523\/JNEUROSCI.0582-08.2008","article-title":"Dissociation of metabolic and neurovascular responses to levodopa in the treatment of Parkinson's disease","volume":"28","author":"Hirano","year":"2008","journal-title":"J. Neurosci."},{"key":"2021111720521465800_B39","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.neuroimage.2012.02.066","article-title":"Impact of L-DOPA treatment on regional cerebral blood flow and metabolism in the basal ganglia in a rat model of Parkinson's disease","volume":"61","author":"Ohlin","year":"2012","journal-title":"NeuroImage"},{"key":"2021111720521465800_B40","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1002\/mds.23616","article-title":"AFQ056 treatment of levodopa-induced dyskinesias: results of 2 randomized controlled trials","volume":"26","author":"Berg","year":"2011","journal-title":"Mov. Disord."},{"key":"2021111720521465800_B41","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.parkreldis.2011.01.008","article-title":"The acute antiparkinsonian and antidyskinetic effect of AFQ056, a novel metabotropic glutamate receptor type\u00a05 antagonist, in L-Dopa-treated parkinsonian monkeys","volume":"17","author":"Gregoire","year":"2011","journal-title":"Parkinsonism Relat. Disord."},{"key":"2021111720521465800_B42","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1124\/jpet.110.166629","article-title":"Reduction of l-DOPA-induced dyskinesia by the selective metabotropic glutamate receptor 5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease","volume":"333","author":"Johnston","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021111720521465800_B43","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.neuropharm.2009.12.024","article-title":"Effect of the metabotropic glutamate receptor type\u00a05 antagonists MPEP and MTEP in parkinsonian monkeys","volume":"58","author":"Morin","year":"2010","journal-title":"Neuropharmacology"},{"key":"2021111720521465800_B44","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.nbd.2010.05.001","article-title":"A mGluR5 antagonist under clinical development improves L-DOPA-induced dyskinesia in parkinsonian rats and monkeys","volume":"39","author":"Rylander","year":"2010","journal-title":"Neurobiol. Dis."},{"key":"2021111720521465800_B45","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1002\/mds.25561","article-title":"AFQ056 in Parkinson patients with levodopa-induced dyskinesia: 13-week, randomized, dose-finding study","volume":"28","author":"Stocchi","year":"2013","journal-title":"Mov. Disord."},{"key":"2021111720521465800_B46","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.expneurol.2013.09.003","article-title":"Modulating mGluR5 and 5-HT1A\/1B receptors to treat L-DOPA-induced dyskinesia: effects of combined treatment and possible mechanisms of action","volume":"250","author":"Iderberg","year":"2013","journal-title":"Exp. Neurol."},{"key":"2021111720521465800_B47","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.neuropharm.2012.03.022","article-title":"Synergy between L-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: implications for Parkinson's disease treatment and dyskinesia","volume":"66","author":"Bennouar","year":"2013","journal-title":"Neuropharmacology"},{"key":"2021111720521465800_B48","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1124\/jpet.111.187443","article-title":"The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease","volume":"340","author":"Jones","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021111720521465800_B49","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1124\/jpet.112.196063","article-title":"A potent and selective metabotropic glutamate receptor 4 positive allosteric modulator improves movement in rodent models of Parkinson's disease","volume":"343","author":"Le Poul","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021111720521465800_B50","doi-asserted-by":"crossref","first-page":"339","DOI":"10.3233\/JPD-2011-11066","article-title":"Activation of metabotropic glutamate 4 receptors decreases L-DOPA-induced dyskinesia in a mouse model of Parkinson's disease","volume":"1","author":"Lopez","year":"2011","journal-title":"J. Parkinson's Dis."}],"container-title":["Biochemical Society Transactions"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article-pdf\/42\/2\/600\/487469\/bst0420600.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article-pdf\/42\/2\/600\/487469\/bst0420600.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T01:35:26Z","timestamp":1637199326000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article\/42\/2\/600\/66987\/Glutamatergic-pathways-as-a-target-for-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,3,20]]},"references-count":50,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2014,3,20]]},"published-print":{"date-parts":[[2014,4,1]]}},"URL":"https:\/\/doi.org\/10.1042\/bst20140006","relation":{},"ISSN":["0300-5127","1470-8752"],"issn-type":[{"value":"0300-5127","type":"print"},{"value":"1470-8752","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,3,20]]}}}