Abstract
The current standard treatment for Parkinson disease focuses on restoring striatal dopamine levels using l-3,4-dihydroxyphenylalanine (l-DOPA). However, disease progression and chronic treatment are associated with motor side effects such as l-DOPA-induced dyskinesia (LID). Dopamine receptor function is strongly associated with the mechanisms underlying LID. In fact, increased D1R signaling is associated with this motor side effect. Compelling evidence demonstrates that dopamine receptors in the striatum can form heteromeric complexes, and heteromerization can lead to changes in the functional and pharmacological properties of receptors compared to their monomeric subtypes. Currently, the most promising strategy for therapeutic intervention in dyskinesia originates from investigations of the D1R–D3R heteromers. Interestingly, there is a correlation between the expression of D1R–D3R heteromers and the development of LID. Moreover, D3R stimulation can potentiate the D1R signaling pathway. The aim of this review is to summarize current knowledge of the distinct roles of heteromeric dopaminergic receptor complexes in LID.
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References
Alcacer C, Andreoli L, Sebastianutto I et al (2017) Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy. J Clin Invest 127:720–734. https://doi.org/10.1172/JCI90132
Ares-Santos S, Granado N, Moratalla R (2013) The role of dopamine receptors in the neurotoxicity of methamphetamine. J Intern Med 273:437–453. https://doi.org/10.1111/joim.12049
Bagetta V, Sgobio C, Pendolino V et al (2012) Rebalance of striatal NMDA/AMPA receptor ratio underlies the reduced emergence of dyskinesia during D2-like dopamine agonist treatment in experimental Parkinson’s disease. J Neurosci 32:17921–17931. https://doi.org/10.1523/JNEUROSCI.2664-12.2012
Bateup HS, Santini E, Shen W et al (2010) Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors. Proc Natl Acad Sci USA 107:14845–14850. https://doi.org/10.1073/pnas.1009874107
Beaulieu JM, Sotnikova TD, Yao WD et al (2004) Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc Natl Acad Sci USA 101:5099–50104
Beaulieu JM, Espinoza S, Gainetdinov RR (2015) Dopamine receptors—IUPHAR review 13. Br J Pharmacol 172:1–23. https://doi.org/10.1111/bph.12906
Berthet A, Porras G, Doudnikoff E et al (2009) Pharmacological analysis demonstrates dramatic alteration of D1 dopamine receptor neuronal distribution in the rat analog of l-DOPA-induced dyskinesia. J Neurosci 29:4829–4835. https://doi.org/10.1523/JNEUROSCI.5884-08.2009
Bézard E, Ferry S, Mach U et al (2003) Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function. Nat Med 9:762–767. https://doi.org/10.1038/nm875
Boraud T, Bezard E, Bioulac B, Gross CE (2001) Dopamine agonist-induced dyskinesias are correlated to both firing pattern and frequency alterations of pallidal neurones in the MPTP-treated monkey. Brain 124:546–557
Bordet R, Ridray S, Schwartz JC, Sokoloff P (2000) Involvement of the direct striatonigral pathway in levodopa-induced sensitization in 6-hydroxydopamine-lesioned rats. Eur J Neurosci 12:2117–2123
Cenci MA, Lee CS, Björklund A (1998) l-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA. Eur J Neurosci 10:2694–2706. https://doi.org/10.1046/j.1460-9568.1998.00285.x
Cortés A, Moreno E, Rodríguez-Ruiz M et al (2016) Targeting the dopamine D3 receptor: an overview of drug design strategies. Expert Opin Drug Discov 11:641–664. https://doi.org/10.1080/17460441.2016.1185413
Cote SR, Chitravanshi VC, Bleickardt C et al (2014) Overexpression of the dopamine D3 receptor in the rat dorsal striatum induces dyskinetic behaviors. Behav Brain Res 263:46–50. https://doi.org/10.1016/j.bbr.2014.01.011
Cruz-Trujillo R, Avalos-Fuentes A, Rangel-Barajas C et al (2013) D3 dopamine receptors interact with dopamine D1 but not D4 receptors in the GABAergic terminals of the SNr of the rat. Neuropharmacology 67:370–378. https://doi.org/10.1016/j.neuropharm.2012.11.032
Darmopil S, Martín AB, De Diego IR et al (2009) Genetic inactivation of dopamine D1 but not D2 receptors inhibits l-DOPA-induced dyskinesia and histone activation. Biol Psychiatry 66:603–613. https://doi.org/10.1016/j.biopsych.2009.04.025
De Deurwaerdère P, Di Giovanni G, Millan MJ (2017) Expanding the repertoire of l-DOPA’s actions: a comprehensive review of its functional neurochemistry. Prog Neurobiol 151:57–100. https://doi.org/10.1016/j.pneurobio.2016.07.002
Ding Y, Restrepo J, Won L et al (2007) Chronic 3,4-dihydroxyphenylalanine treatment induces dyskinesia in aphakia mice, a novel genetic model of Parkinson’s disease. Neurobiol Dis 27:11–23. https://doi.org/10.1016/j.nbd.2007.03.013
Dumartin B, Caillé I, Gonon F, Bloch B (1998) Internalization of D1 dopamine receptor in striatal neurons in vivo as evidence of activation by dopamine agonists. J Neurosci 18:1650–1661
Dupré DJ, Hébert TE (2006) Biosynthesis and trafficking of seven transmembrane receptor signalling complexes. Cell Signal 18:1549–1559. https://doi.org/10.1016/j.cellsig.2006.03.009
F Hernández L, Castela I, Ruiz-DeDiego I et al (2017) Striatal activation by optogenetics induces dyskinesias in the 6-hydroxydopamine rat model of Parkinson disease. Mov Disord 32:530–537. https://doi.org/10.1002/mds.26947
Farré D, Muñoz A, Moreno E et al (2015) Stronger dopamine D1 receptor-mediated neurotransmission in dyskinesia. Mol Neurobiol 52:1408–1420. https://doi.org/10.1007/s12035-014-8936-x
Ferré S, Baler R, Bouvier M et al (2009) Building a new conceptual framework for receptor heteromers. Nat Chem Biol 5:131–134. https://doi.org/10.1038/nchembio0309-131
Ferré S, Lluis C, Lanciego JL, Franco R (2010) Prime time for G-protein-coupled receptor heteromers as therapeutic targets for CNS disorders: the dopamine D1–D2 receptor heteromer. CNS Neurol Disord Drug Targets 9:596–600
Fieblinger T, Cenci MA (2015) Zooming in on the small: the plasticity of striatal dendritic spines in l-DOPA-induced dyskinesia. Mov Disord 30:484–493. https://doi.org/10.1002/mds.26139
Fiorentini C, Busi C, Gorruso E et al (2008) Reciprocal regulation of dopamine D1 and D3 receptor function and trafficking by heterodimerization. Mol Pharmacol 74:59–69. https://doi.org/10.1124/mol.107.043885
Fiorentini C, Busi C, Spano P, Missale C (2010) Dimerization of dopamine D1 and D3 receptors in the regulation of striatal function. Curr Opin Pharmacol 10:87–92. https://doi.org/10.1016/j.coph.2009.09.008
Fiorentini C, Mattanza C, Collo G et al (2011) The tyrosine phosphatase Shp-2 interacts with the dopamine D(1) receptor and triggers D(1)-mediated Erk signaling in striatal neurons. J Neurochem 117:253–263. https://doi.org/10.1111/j.1471-4159.2011.07196.x
Fiorentini C, Savoia P, Savoldi D et al (2013) Persistent activation of the D1R/Shp-2/Erk1/2 pathway in l-DOPA-induced dyskinesia in the 6-hydroxy-dopamine rat model of Parkinson’s disease. Neurobiol Dis 54:339–348. https://doi.org/10.1016/j.nbd.2013.01.005
Fiorentini C, Savoia P, Bono F et al (2015) The D3 dopamine receptor: from structural interactions to function. Eur Neuropsychopharmacol 25:1462–1469. https://doi.org/10.1016/j.euroneuro.2014.11.021
Fiorentini C, Savoia P, Savoldi D et al (2016) Shp-2 knockdown prevents l-dopa-induced dyskinesia in a rat model of Parkinson’s disease. Mov Disord 31:512–520. https://doi.org/10.1002/mds.26581
Flores G, Barbeau D, Quirion R, Srivastava LK (1996) Decreased binding of dopamine D3 receptors in limbic subregions after neonatal bilateral lesion of rat hippocampus. J Neurosci 16:2020–2026
Flores G, Liang JJ, Sierra A et al (1999) Expression of dopamine receptors in the subthalamic nucleus of the rat: characterization using reverse transcriptase-polymerase chain reaction and autoradiography. Neuroscience 91:549–556
Frederick AL, Yano H, Trifilieff P et al (2015) Evidence against dopamine D1/D2 receptor heteromers. Mol Psychiatry 20:1373–1385. https://doi.org/10.1038/mp.2014.166
Fuxe K, Guidolin D, Agnati LF, Borroto-Escuela DO (2015) Dopamine heteroreceptor complexes as therapeutic targets in Parkinson’s disease. Expert Opin Ther Targets 19:377–398. https://doi.org/10.1517/14728222.2014.981529
Gagnon D, Petryszyn S, Sanchez MG et al (2017) Striatal neurons expressing D1 and D2 receptors are morphologically distinct and differently affected by dopamine denervation in mice. Sci Rep 7:41432. https://doi.org/10.1038/srep41432
Gerfen CR, Surmeier DJ (2011) Modulation of striatal projection systems by dopamine. Annu Rev Neurosci 34:441–466. https://doi.org/10.1146/annurev-neuro-061010-113641
González-Aparicio R, Moratalla R (2014) Oleoylethanolamide reduces l-DOPA-induced dyskinesia via TRPV1 receptor in a mouse model of Parkinson’s disease. Neurobiol Dis 62:416–425. https://doi.org/10.1016/j.nbd.2013.10.008
Granado N, Ares-Santos S, Moratalla R (2013) Methamphetamine and Parkinson’s disease. Parkinsons Dis 2013:308052. https://doi.org/10.1155/2013/308052
Guigoni C, Aubert I, Li Q et al (2005) Pathogenesis of levodopa-induced dyskinesia: focus on D1 and D3 dopamine receptors. Parkinsonism Relat Disord 11(Suppl 1):S25–S29. https://doi.org/10.1016/j.parkreldis.2004.11.005
Guitart X, Navarro G, Moreno E et al (2014) Functional selectivity of allosteric interactions within G protein-coupled receptor oligomers: the dopamine D1–D3 receptor heterotetramer. Mol Pharmacol 86:417–429. https://doi.org/10.1124/mol.114.093096
Hasbi A, Fan T, Alijaniaram M et al (2009) Calcium signaling cascade links dopamine D1–D2 receptor heteromer to striatal BDNF production and neuronal growth. Proc Natl Acad Sci USA 106:21377–21382. https://doi.org/10.1073/pnas.0903676106
Henley JM, Moratallo R, Hunt SP, Barnard EA (1989) Localization and quantitative autoradiography of glutamatergic ligand binding sites in chick brain. Eur J Neurosci 1:516–523
Heumann R, Moratalla R, Herrero MT et al (2014) Dyskinesia in Parkinson’s disease: mechanisms and current non-pharmacological interventions. J Neurochem 130:472–489. https://doi.org/10.1111/jnc.12751
Huot P, Johnston TH, Koprich JB et al (2012) L-745,870 reduces l-DOPA-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson’s disease. J Pharmacol Exp Ther 342:576–585. https://doi.org/10.1124/jpet.112.195693
Kravitz AV, Freeze BS, Parker PRL et al (2010) Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 466:622–626. https://doi.org/10.1038/nature09159
Kumar R, Riddle L, Griffin SA et al (2009) Evaluation of the D3 dopamine receptor selective antagonist PG01037 on l-dopa-dependent abnormal involuntary movements in rats. Neuropharmacology 56:944–955. https://doi.org/10.1016/j.neuropharm.2009.01.020
Lee SP, So CH, Rashid AJ et al (2004) Dopamine D1 and D2 receptor co-activation generates a novel phospholipase C-mediated calcium signal. J Biol Chem 279:35671–35678. https://doi.org/10.1074/jbc.M401923200
Lisman J, Yasuda R, Raghavachari S (2012) Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci 13:169–182. https://doi.org/10.1038/nrn3192
Maggio R, Scarselli M, Capannolo M, Millan MJ (2015) Novel dimensions of D3 receptor function: focus on heterodimerisation, transactivation and allosteric modulation. Eur Neuropsychopharmacol 25:1470–1479. https://doi.org/10.1016/j.euroneuro.2014.09.016
Marcellino D, Ferré S, Casadó V et al (2008) Identification of dopamine D1–D3 receptor heteromers. Indications for a role of synergistic D1–D3 receptor interactions in the striatum. J Biol Chem 283:26016–26025. https://doi.org/10.1074/jbc.M710349200
Matsuda W, Furuta T, Nakamura KC et al (2009) Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J Neurosci 29:444–453. https://doi.org/10.1523/JNEUROSCI.4029-08.2009
Mela F, Millan MJ, Brocco M, Morari M (2010) The selective D(3) receptor antagonist, S33084, improves parkinsonian-like motor dysfunction but does not affect l-DOPA-induced dyskinesia in 6-hydroxydopamine hemi-lesioned rats. Neuropharmacology 58:528–536. https://doi.org/10.1016/j.neuropharm.2009.08.017
Mela F, Marti M, Bido S et al (2012) In vivo 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. Neurobiol Dis 45:573–582. https://doi.org/10.1016/j.nbd.2011.09.015
Millan MJ, Dekeyne A, Rivet JM et al (2000) S33084, a novel, potent, selective, and competitive antagonist at dopamine D(3)-receptors: II. Functional and behavioral profile compared with GR218,231 and L741,626. J Pharmacol Exp Ther 293:1063–1073
Monville C, Torres EM, Dunnett SB (2005) Validation of the l-dopa-induced dyskinesia in the 6-OHDA model and evaluation of the effects of selective dopamine receptor agonists and antagonists. Brain Res Bull 68:16–23. https://doi.org/10.1016/j.brainresbull.2004.10.011
Moratalla R, Solís O, Suárez LM (2017) Morphological plasticity in the striatum associated with dopamine dysfunction. In: Handbook of basal ganglia structure and function, 2nd edn. Elsevier, New York, pp 755–770. https://doi.org/10.1016/b978-0-12802206-1.00037-4
Murer MG, Moratalla R (2011) Striatal signaling in l-DOPA-induced dyskinesia: common mechanisms with drug abuse and long term memory involving D1 dopamine receptor stimulation. Front Neuroanat 5:51. https://doi.org/10.3389/fnana.2011.00051
Pavón N, Martín AB, Mendialdua A, Moratalla R (2006) ERK phosphorylation and FosB expression are associated with l-DOPA-induced dyskinesia in hemiparkinsonian mice. Biol Psychiatry 59:64–74. https://doi.org/10.1016/j.biopsych.2005.05.044
Payer DE, Guttman M, Kish SJ et al (2016) D3 dopamine receptor-preferring [11C]PHNO PET imaging in Parkinson patients with dyskinesia. Neurology 86:224–230. https://doi.org/10.1212/WNL.0000000000002285
Perez XA, Zhang D, Bordia T, Quik M (2017) Striatal D1 medium spiny neuron activation induces dyskinesias in parkinsonian mice. Mov Disord 32:538–548. https://doi.org/10.1002/mds.26955
Perreault ML, Hasbi A, Alijaniaram M et al (2010) The dopamine D1–D2 receptor heteromer localizes in dynorphin/enkephalin neurons: increased high affinity state following amphetamine and in schizophrenia. J Biol Chem 285:36625–36634. https://doi.org/10.1074/jbc.M110.159954
Perreault ML, Hasbi A, O’Dowd BF, George SR (2011) The dopamine D1–D2 receptor heteromer in striatal medium spiny neurons: evidence for a third distinct neuronal pathway in Basal Ganglia. Front Neuroanat 5:31. https://doi.org/10.3389/fnana.2011.00031
Perreault ML, Fan T, Alijaniaram M et al (2012) Dopamine D1–D2 receptor heteromer in dual phenotype GABA/glutamate-coexpressing striatal medium spiny neurons: regulation of BDNF, GAD67 and VGLUT1/2. PLoS ONE 7:e33348. https://doi.org/10.1371/journal.pone.0033348
Perreault ML, Hasbi A, O’Dowd BF, George SR (2014) Heteromeric dopamine receptor signaling complexes: emerging neurobiology and disease relevance. Neuropsychopharmacology 39:156–168. https://doi.org/10.1038/npp.2013.148
Perreault ML, Hasbi A, Shen MYF et al (2016) Disruption of a dopamine receptor complex amplifies the actions of cocaine. Eur Neuropsychopharmacol 26:1366–1377. https://doi.org/10.1016/j.euroneuro.2016.07.008
Peterson SM, Pack TF, Wilkins AD et al (2015) Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor. Proc Natl Acad Sci USA 112:7097–7102. https://doi.org/10.1073/pnas.1502742112
Picconi B, Centonze D, Håkansson K et al (2003) Loss of bidirectional striatal synaptic plasticity in l-DOPA-induced dyskinesia. Nat Neurosci 6:501–506. https://doi.org/10.1038/nn1040
Porras G, Berthet A, Dehay B et al (2012) PSD-95 expression controls l-DOPA dyskinesia through dopamine D1 receptor trafficking. J Clin Investig 122:3977–3989. https://doi.org/10.1172/JCI59426
Rangel-Barajas C, Silva I, Lopéz-Santiago LM et al (2011) l-DOPA-induced dyskinesia in hemiparkinsonian rats is associated with up-regulation of adenylyl cyclase type V/VI and increased GABA release in the substantia nigra reticulata. Neurobiol Dis 41:51–61. https://doi.org/10.1016/j.nbd.2010.08.018
Rangel-Barajas C, Coronel I, Florán B (2015) Dopamine receptors and neurodegeneration. Aging Dis 6:349–368. https://doi.org/10.14336/AD.2015.0330
Rashid AJ, So CH, Kong MM et al (2007) D1–D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. Proc Natl Acad Sci USA 104:654–659
Rico AJ, Dopeso-Reyes IG, Martínez-Pinilla E et al (2017) Neurochemical evidence supporting dopamine D1–D2 receptor heteromers in the striatum of the long-tailed macaque: changes following dopaminergic manipulation. Brain Struct Funct 222:1767–1784. https://doi.org/10.1007/s00429-016-1306-x
Rivera A, Cuéllar B, Girón FJ et al (2002) Dopamine D4 receptors are heterogeneously distributed in the striosomes/matrix compartments of the striatum. J Neurochem 80:219–229
Rivera A, Trías S, Peñafiel A et al (2003) Expression of D4 dopamine receptors in striatonigral and striatopallidal neurons in the rat striatum. Brain Res 989:35–41
Ruiz-DeDiego I, Mellstrom B, Vallejo M et al (2015) Activation of DREAM (downstream regulatory element antagonistic modulator), a calcium-binding protein, reduces l-DOPA-induced dyskinesias in mice. Biol Psychiatry 77:95–105. https://doi.org/10.1016/j.biopsych.2014.03.023
Sánchez-Pernaute R, Jenkins BG, Choi J-K et al (2007) In vivo evidence of D3 dopamine receptor sensitization in parkinsonian primates and rodents with l-DOPA-induced dyskinesias. Neurobiol Dis 27:220–227. https://doi.org/10.1016/j.nbd.2007.04.016
Santini E, Valjent E, Usiello A et al (2007) Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in l-DOPA-induced dyskinesia. J Neurosci 27:6995–7005. https://doi.org/10.1523/JNEUROSCI.0852-07.2007
Santini E, Alcacer C, Cacciatore S et al (2009) l-DOPA activates ERK signaling and phosphorylates histone H3 in the striatonigral medium spiny neurons of hemiparkinsonian mice. J Neurochem 108:621–633. https://doi.org/10.1111/j.1471-4159.2008.05831.x
Scarselli M, Novi F, Schallmach E et al (2001) D2/D3 dopamine receptor heterodimers exhibit unique functional properties. J Biol Chem 276:30308–30314. https://doi.org/10.1074/jbc.M102297200
Sebastianutto I, Maslava N, Hopkins CR, Cenci MA (2016) Validation of an improved scale for rating l-DOPA-induced dyskinesia in the mouse and effects of specific dopamine receptor antagonists. Neurobiol Dis 96:156–170. https://doi.org/10.1016/j.nbd.2016.09.001
Silverdale MA, Nicholson SL, Ravenscroft P et al (2004) Selective blockade of D(3) dopamine receptors enhances the anti-parkinsonian properties of ropinirole and levodopa in the MPTP-lesioned primate. Exp Neurol 188:128–138. https://doi.org/10.1016/j.expneurol.2004.03.022
Sokoloff P, Giros B, Martres MP et al (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146–151. https://doi.org/10.1038/347146a0
Solís O, Espadas I, Del-Bel EA, Moratalla R (2015) Nitric oxide synthase inhibition decreases l-DOPA-induced dyskinesia and the expression of striatal molecular markers in Pitx3(−/−) aphakia mice. Neurobiol Dis 73:49–59. https://doi.org/10.1016/j.nbd.2014.09.010
Solís O, García-Sanz P, Herranz AS et al (2016) l-DOPA reverses the increased free amino acids tissue levels induced by dopamine depletion and rises GABA and tyrosine in the striatum. Neurotox Res 30:67–75. https://doi.org/10.1007/s12640-016-9612-x
Solís O, García-Montes J-R, Garcia-Sanz P et al (2017a) Human COMT over-expression confers a heightened susceptibility to dyskinesia in mice. Neurobiol Dis 102:133–139. https://doi.org/10.1016/j.nbd.2017.03.006
Solís O, Garcia-Montes JR, González-Granillo A et al (2017b) Dopamine D3 receptor modulates l-DOPA-induced dyskinesia by targeting D1 receptor-mediated striatal signaling. Cereb Cortex 27:435–446. https://doi.org/10.1093/cercor/bhv231
Suarez LM, Solis O, Aguado C et al (2016) l-DOPA oppositely regulates synaptic strength and spine morphology in D1 and D2 striatal projection neurons in dyskinesia. Cereb Cortex 26:4253–4264. https://doi.org/10.1093/cercor/bhw263
Suarez LM, Alberquilla S, García-Montes JR, Moratalla R (2018) Differential synaptic remodeling by dopamine in direct and indirect striatal projection neurons in Pitx3−/− mice, a genetic model of Parkinson’s disease. J Neurosci (in press)
Suárez LM, Solís O, Caramés JM et al (2014) l-DOPA treatment selectively restores spine density in dopamine receptor D2-expressing projection neurons in dyskinetic mice. Biol Psychiatry 75:711–722. https://doi.org/10.1016/j.biopsych.2013.05.006
Surmeier DJ, Obeso JA, Halliday GM (2017) Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 18:101–113. https://doi.org/10.1038/nrn.2016.178
Verma V, Hasbi A, O’Dowd BF, George SR (2010) Dopamine D1–D2 receptor heteromer-mediated calcium release is desensitized by D1 receptor occupancy with or without signal activation: dual functional regulation by G protein-coupled receptor kinase 2. J Biol Chem 285:35092–35103. https://doi.org/10.1074/jbc.M109.088625
Visanji NP, Fox SH, Johnston T et al (2009) Dopamine D3 receptor stimulation underlies the development of l-DOPA-induced dyskinesia in animal models of Parkinson’s disease. Neurobiol Dis 35:184–192. https://doi.org/10.1016/j.nbd.2008.11.010
Westin JE, Vercammen L, Strome EM et al (2007) Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of l-DOPA-induced dyskinesia and the role of dopamine D1 receptors. Biol Psychiatry 62:800–810. https://doi.org/10.1016/j.biopsych.2006.11.032
Xu M, Koeltzow TE, Santiago GT et al (1997) Dopamine D3 receptor mutant mice exhibit increased behavioral sensitivity to concurrent stimulation of D1 and D2 receptors. Neuron 19:837–848. https://doi.org/10.1016/S0896-6273(00)80965-4
Zhang S, Xie C, Wang Q, Liu Z (2014) Interactions of CaMKII with dopamine D2 receptors: roles in levodopa-induced dyskinesia in 6-hydroxydopamine lesioned Parkinson’s rats. Sci Rep 4:6811. https://doi.org/10.1038/srep06811
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This work was supported by grants from the Spanish Ministeries of Economía y Competitividad, Sanidad Política Social e Igualdad and ISCIII CIBERNED: SAF2016-78207-R, PCIN2015-098, CB06/05/0055 and PI2015-2/02 to RM.
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Solís, O., Moratalla, R. Dopamine receptors: homomeric and heteromeric complexes in l-DOPA-induced dyskinesia. J Neural Transm 125, 1187–1194 (2018). https://doi.org/10.1007/s00702-018-1852-x
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DOI: https://doi.org/10.1007/s00702-018-1852-x