Brain Structure and Function

, Volume 221, Issue 7, pp 3675–3691 | Cite as

Serotonin hyperinnervation of the striatum with high synaptic incidence in parkinsonian monkeys

  • D. Gagnon
  • L. Gregoire
  • T. Di Paolo
  • Martin ParentEmail author
Original Article


The chronic use of L-Dopa for alleviating the motor symptoms of Parkinson’s disease often produces adverse effects such as dyskinesia. Unregulated release of dopamine by serotonin axons following L-Dopa administration is a major presynaptic determinant of these abnormal involuntary movements. The present study was designed to characterize the reorganization of serotonin striatal afferents following dopaminergic denervation in a primate model of Parkinson’s disease. Our sample comprised eight cynomolgus monkeys: four that were rendered parkinsonian following MPTP administration and four controls. The state of striatal serotonin and dopamine innervation was evaluated by means of immunohistochemistry with antibodies against serotonin transporter (SERT) and tyrosine hydroxylase. A detailed stereological investigation revealed a significant increase in the number of serotonin axon varicosities in the striatum of MPTP-intoxicated monkeys. This increase is particularly pronounced in the sensorimotor territory of the striatum, where the dopamine denervation is the most severe. Electron microscopic examinations indicate that, in contrast to the nucleus accumbens where the dopamine innervation is preserved, the SERT+ axon varicosities observed in the sensorimotor territory of the putamen establish twice as many synaptic contacts in MPTP-intoxicated monkeys than in controls. These findings demonstrate the highly plastic nature of the serotonin striatal afferent projections, a feature that becomes particularly obvious in the absence of striatal dopamine. Although the number of dorsal raphe serotonin neurons remains constant in parkinsonian monkeys, as shown in the present study, their ascending axonal projections undergo marked proliferative and synaptic adaptive changes that might play a significant role in the potential unregulated and ectopic release of dopamine by serotonin axons after L-Dopa treatment of Parkinson’s disease.


Basal ganglia Primates Stereology Electron microscopy Axonal sprouting Dorsal raphe nucleus 



Trochlear nucleus


Serotonin, 5-hydroxytryptamine


Aromatic L-amino acid decarboxylase


Anterior commissure


Nucleus accumbens


Cerebral aqueduct


Caudate nucleus




3,3′ diaminobenzidine tetrahydrochloride


Dopamine transporter


Dendritic branch


Dorsal raphe nucleus


Internal capsule




L-Dopa-induced dyskinesia




Median raphe nucleus


Sodium phosphate buffer


Sodium phosphate-buffered saline


Periaqueducal gray


Positron emission tomography






Room temperature


Superior colliculus


Serotonin transporter


Substantia nigra pars compacta


Tris-saline buffer


Tyrosine hydroxylase


Tryptophan hydroxylase


Vesicular monoamine transporter 2


Decussation of superior cerebellar peduncle



This study was supported by research grant from the Canadian Institutes of Health Research (CIHR MOP-115008). MP received a career award from the “Fonds de Recherche du Québec, Santé (FRQS)”. DG was the recipient of a PhD fellowship from FRQ-S. The authors are grateful to Marie-Josée Wallman, Caroline Côté and Marc Morissette for technical assistance. The authors have no conflict of interest to declare.

Supplementary material

429_2015_1125_MOESM1_ESM.pdf (63 kb)
Online resource 1 Information on control and MPTP-intoxicated monkeys used in this study. Abbreviations: NA: Not applicable (PDF 63 kb)
429_2015_1125_MOESM2_ESM.pdf (316 kb)
Online resource 2 Immunoreactivity for the dopamine transporter (DAT) in the striatum of control and MPTP-intoxicated monkeys. (A) Schematic representations of the striatal functional territories, at three anteroposterior levels, each identified with its own color (see Fig. 2 legend for further details). (B, C) Histograms of optical density measurements of DAT immunoreactivity in the sensorimotor (B), the associative and the limbic (C) striatal territories, at the three anteroposterior levels examined. Optical density measurements indicate a significant decrease of DAT immunoreactivity throughout the striatum, except in the limbic striatal territory. * P < 0.05 using Mann-Whitney U test (PDF 315 kb)
429_2015_1125_MOESM3_ESM.pdf (298 kb)
Online resource 3 Number of SERT immunoreactive axon varicosities per 10 µm of axon in the various functional territories of the striatum, in controls and MPTP-intoxicated monkeys. (A) Schematic representations of the striatal functional territories, at the three anteroposterior levels, each identified with its own color (see Fig. 2 legend for further details). (B, C) Histograms showing the number of SERT+ axon varicosities per 10 µm of axons in the sensorimotor (B), the associative and limbic (C) striatal territories, at the three anteroposterior levels examined. No significant differences were observed between MPTP and control animals, suggesting that the sprouting of SERT+ varicose axons causes the increase in the density of SERT+ axon varicosities (PDF 298 kb)


  1. Agid Y (1991) Parkinson’s disease: pathophysiology. Lancet 337:1321–1324CrossRefPubMedGoogle Scholar
  2. Albin RL, Koeppe RA, Bohnen NI, Wernette K, Kilbourn MA, Frey KA (2008) Spared caudal brainstem SERT binding in early Parkinson’s disease. J Cereb Blood Flow Metab 28:441–444. doi: 10.1038/sj.jcbfm.9600599 CrossRefPubMedGoogle Scholar
  3. Arai R, Karasawa N, Geffard M, Nagatsu T, Nagatsu I (1994) Immunohistochemical evidence that central serotonin neurons produce dopamine from exogenous L-DOPA in the rat, with reference to the involvement of aromatic L-amino acid decarboxylase. Brain Res 667:295–299CrossRefPubMedGoogle Scholar
  4. Arai R, Karasawa N, Geffard M, Nagatsu I (1995) L-DOPA is converted to dopamine in serotonergic fibers of the striatum of the rat: a double-labeling immunofluorescence study. Neurosci Lett 195:195–198CrossRefPubMedGoogle Scholar
  5. Arluison M, de la Manche IS (1980) High-resolution radioautographic study of the serotonin innervation of the rat corpus striatum after intraventricular administration of [3H]5-hydroxytryptamine. Neuroscience 5:229–240CrossRefPubMedGoogle Scholar
  6. Azmitia EC, Gannon PJ (1986) The primate serotonergic system: a review of human and animal studies and a report on Macaca fascicularis. Adv Neurol 43:407–468PubMedGoogle Scholar
  7. Balcioglu A, Zhang K, Tarazi FI (2003) Dopamine depletion abolishes apomorphine- and amphetamine-induced increases in extracellular serotonin levels in the striatum of conscious rats: a microdialysis study. Neuroscience 119:1045–1053CrossRefPubMedGoogle Scholar
  8. Beaudet A, Sotelo C (1981) Synaptic remodeling of serotonin axon terminals in rat agranular cerebellum. Brain Res 206:305–329CrossRefPubMedGoogle Scholar
  9. Beaudoin-Gobert M, Epinat J, Metereau E, Duperrier S, Neumane S, Ballanger B, Lavenne F, Liger F, Tourvielle C, Bonnefoi F, Costes N, Bars DL, Broussolle E, Thobois S, Tremblay L, Sgambato-Faure V (2015) Behavioural impact of a double dopaminergic and serotonergic lesion in the non-human primate. Brain J Neurol 138:2632–2647. doi: 10.1093/brain/awv183
  10. Bedard C, Wallman MJ, Pourcher E, Gould PV, Parent A, Parent M (2011) Serotonin and dopamine striatal innervation in Parkinson’s disease and Huntington’s chorea. Parkinsonism Relat Disord 17:593–598. doi: 10.1016/j.parkreldis.2011.05.012 CrossRefPubMedGoogle Scholar
  11. Berger TW, Kaul S, Stricker EM, Zigmond MJ (1985) Hyperinnervation of the striatum by dorsal raphe afferents after dopamine-depleting brain lesions in neonatal rats. Brain Res 336:354–358. doi:0006-8993(85)90667-5 [pii]Google Scholar
  12. Bernheimer H, Birkmayer W, Hornykiewicz O (1961) Distribution of 5-hydroxytryptamine (serotonin) in the human brain and its behavior in patients with Parkinson’s syndrome. Klin Wochenschr 39:1056–1059CrossRefPubMedGoogle Scholar
  13. Birkmayer W, Birkmayer JD (1987) Dopamine action and disorders of neurotransmitter balance. Gerontology 33:168–171CrossRefPubMedGoogle Scholar
  14. Boulet S, Mounayar S, Poupard A, Bertrand A, Jan C, Pessiglione M, Hirsch EC, Feuerstein C, Francois C, Feger J, Savasta M, Tremblay L (2008) Behavioral recovery in MPTP-treated monkeys: neurochemical mechanisms studied by intrastriatal microdialysis. J Neurosci Off J Soc Neurosci 28:9575–9584. doi: 10.1523/JNEUROSCI.3465-08.200828/38/9575 CrossRefGoogle Scholar
  15. Bowden DM, Martin RF (2000) Primate brain maps: structure of the macaque brain. Elsevier, AmsterdamGoogle Scholar
  16. Braak H, Rub U, Gai WP, Del Tredici K (2003) Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110:517–536. doi: 10.1007/s00702-002-0808-2 CrossRefPubMedGoogle Scholar
  17. Bubser M, Backstrom JR, Sanders-Bush E, Roth BL, Deutch AY (2001) Distribution of serotonin 5-HT(2A) receptors in afferents of the rat striatum. Synapse 39:297–304. doi: 10.1002/1098-2396(20010315)39:4<297:AID-SYN1012>3.0.CO;2-Q CrossRefPubMedGoogle Scholar
  18. Calabresi P, Ghiglieri V, Mazzocchetti P, Corbelli I, Picconi B (2015) Levodopa-induced plasticity: a double-edged sword in Parkinson’s disease? Philos Trans R Soc Lond B Biol Sci. doi:20140184 [pii]Google Scholar
  19. Calas A, Besson MJ, Gaughy C, Alonso G, Glowinski J, Cheramy A (1976) Radioautographic study of in vivo incorporation of 3H-monoamines in the cat caudate nucleus: identification of serotoninergic fibers. Brain Res 118:1–13. doi:0006-8993(76)90837-4 [pii]Google Scholar
  20. Calon F, Morissette M, Rajput AH, Hornykiewicz O, Bedard PJ, Di Paolo T (2003) Changes of GABA receptors and dopamine turnover in the postmortem brains of parkinsonians with levodopa-induced motor complications. Mov Disord Off J Mov Disord Soc 18:241–253. doi: 10.1002/mds.10343 CrossRefGoogle Scholar
  21. Carta M, Tronci E (2014) Serotonin system implication in L-DOPA-induced dyskinesia: from animal models to clinical investigations. Front Neurol 5:78. doi: 10.3389/fneur.2014.00078 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Carta M, Carlsson T, Kirik D, Bjorklund A (2007) Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain J Neurol 130:1819–1833. doi: 10.1093/brain/awm082
  23. Carta M, Carlsson T, Munoz A, Kirik D, Bjorklund A (2008a) Involvement of the serotonin system in L-dopa-induced dyskinesias. Parkinsonism Relat Disord 14(Suppl 2):S154–S158. doi: 10.1016/j.parkreldis.2008.04.021 CrossRefPubMedGoogle Scholar
  24. Carta M, Carlsson T, Munoz A, Kirik D, Bjorklund A (2008b) Serotonin-dopamine interaction in the induction and maintenance of L-DOPA-induced dyskinesias. Prog Brain Res 172:465–478. doi: 10.1016/S0079-6123(08)00922-9 CrossRefPubMedGoogle Scholar
  25. Cash R, Raisman R, Ploska A, Agid Y (1985) High and low affinity [3H]imipramine binding sites in control and parkinsonian brains. Eur J Pharmacol 117:71–80CrossRefPubMedGoogle Scholar
  26. Cheshire P, Ayton S, Bertram KL, Ling H, Li A, McLean C, Halliday GM, O’Sullivan SS, Revesz T, Finkelstein DI, Storey E, Williams DR (2015) Serotonergic markers in Parkinson’s disease and levodopa-induced dyskinesias. Mov Disord Off J Mov Disord Soc 30:796–804. doi: 10.1002/mds.26144 CrossRefGoogle Scholar
  27. Chinaglia G, Landwehrmeyer B, Probst A, Palacios JM (1993) Serotoninergic terminal transporters are differentially affected in Parkinson’s disease and progressive supranuclear palsy: an autoradiographic study with [3H]citalopram. Neuroscience 54:691–699CrossRefPubMedGoogle Scholar
  28. Crissman RS, Arce EA, Bennett-Clarke CA, Mooney RD, Rhoades RW (1993) Reduction in the percentage of serotoninergic axons making synapses during the development of the superficial layers of the hamster’s superior colliculus. Brain Res Dev Brain Res 75:131–135CrossRefPubMedGoogle Scholar
  29. Descarries L, Mechawar N (2008) Structural Organization of monoamine and acetylcholine neuron systems in the rat CNS. In: Lajtha A, Vizi ES (eds) Handbook of neurochemistry and molecular neurobiology. Springer US, New York, pp 1–20. doi: 10.1007/978-0-387-30382-6_1
  30. Descarries L, Soghomonian JJ, Garcia S, Doucet G, Bruno JP (1992) Ultrastructural analysis of the serotonin hyperinnervation in adult rat neostriatum following neonatal dopamine denervation with 6-hydroxydopamine. Brain Res 569:1–13CrossRefPubMedGoogle Scholar
  31. Descarries L, Riad M, Parent M (2010) Ultrastructure of the serotonin innervation in the mammalian central nervous system. In: Christian PM, Barry LJ (eds) Handbook of behavioral neuroscience, vol 21. Elsevier, Amsterdam, pp 65–101. doi: 10.1016/S1569-7339(10)70072-2
  32. Eid L, Champigny MF, Parent A, Parent M (2013) Quantitative and ultrastructural study of serotonin innervation of the globus pallidus in squirrel monkeys. Eur J Neurosci 37:1659–1668. doi: 10.1111/ejn.12164 CrossRefPubMedGoogle Scholar
  33. Everett GM, Borcherding JW (1970) L-dopa: effect on concentrations of dopamine, norepinephrine, and serotonin in brains of mice. Science 168:849–850. doi: 10.1126/science.168.3933.849 CrossRefPubMedGoogle Scholar
  34. Fahn S, Libsch LR, Cutler RW (1971) Monoamines in the human neostriatum: topographic distribution in normals and in Parkinson’s disease and their role in akinesia, rigidity, chorea, and tremor. J Neurol Sci 14:427–455CrossRefPubMedGoogle Scholar
  35. Gai WP, Halliday GM, Blumbergs PC, Geffen LB, Blessing WW (1991) Substance P-containing neurons in the mesopontine tegmentum are severely affected in Parkinson’s disease. Brain J Neurol 114 (Pt 5):2253–2267Google Scholar
  36. Gaspar P, Febvret A, Colombo J (1993) Serotonergic sprouting in primate MTP-induced hemiparkinsonism. Exp Brain Res 96:100–106CrossRefPubMedGoogle Scholar
  37. Guerra MJ, Liste I, Labandeira-Garcia JL (1997) Effects of lesions of the nigrostriatal pathway and of nigral grafts on striatal serotonergic innervation in adult rats. NeuroReport 8:3485–3488CrossRefPubMedGoogle Scholar
  38. Gupta M, Felten DL, Gash DM (1984) MPTP alters central catecholamine neurons in addition to the nigrostriatal system. Brain Res Bull 13:737–742CrossRefPubMedGoogle Scholar
  39. Guttman M, Boileau I, Warsh J, Saint-Cyr JA, Ginovart N, McCluskey T, Houle S, Wilson A, Mundo E, Rusjan P, Meyer J, Kish SJ (2007) Brain serotonin transporter binding in non-depressed patients with Parkinson’s disease. Eur J Neurol 14:523–528CrossRefPubMedGoogle Scholar
  40. Halliday GM, Blumbergs PC, Cotton RG, Blessing WW, Geffen LB (1990a) Loss of brainstem serotonin- and substance P-containing neurons in Parkinson’s disease. Brain Res 510:104–107CrossRefPubMedGoogle Scholar
  41. Halliday GM, Li YW, Blumbergs PC, Joh TH, Cotton RG, Howe PR, Blessing WW, Geffen LB (1990b) Neuropathology of immunohistochemically identified brainstem neurons in Parkinson’s disease. Ann Neurol 27:373–385. doi: 10.1002/ana.410270405 CrossRefPubMedGoogle Scholar
  42. Hely MA, Morris JG, Reid WG, Trafficante R (2005) Sydney Multicenter Study of Parkinson’s disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord Off J Mov Disord Soc 20:190–199. doi: 10.1002/mds.20324 CrossRefGoogle Scholar
  43. Hollister AS, Breese GR, Mueller RA (1979) Role of monoamine neural systems in L-dihydroxyphenylalanine-stimulated activity. J Pharmacol Exp Ther 208:37–43PubMedGoogle Scholar
  44. Hornung JP (2003) The human raphe nuclei and the serotonergic system. J Chem Neuroanat 26:331–343CrossRefPubMedGoogle Scholar
  45. Huot P, Johnston TH, Winkelmolen L, Fox SH, Brotchie JM (2012) 5-HT2A receptor levels increase in MPTP-lesioned macaques treated chronically with L-DOPA. Neurobiol Aging 33:194, e195–115 doi: 10.1016/j.neurobiolaging.2010.04.035
  46. Jellinger K (1989) Pathology of Parkinson’s syndrome. In: Calne D (ed) Drugs for the treatment of Parkinson’s disease, vol 88. Handbook of experimental pharmacology. Springer, Berlin Heidelberg, pp 47–112. doi: 10.1007/978-3-642-73899-9_2
  47. Kerenyi L, Ricaurte GA, Schretlen DJ, McCann U, Varga J, Mathews WB, Ravert HT, Dannals RF, Hilton J, Wong DF, Szabo Z (2003) Positron emission tomography of striatal serotonin transporters in Parkinson disease. Arch Neurol 60:1223–1229CrossRefPubMedGoogle Scholar
  48. Kim SE, Choi JY, Choe YS, Choi Y, Lee WY (2003) Serotonin transporters in the midbrain of Parkinson’s disease patients: a study with 123I-beta-CIT SPECT. J Nucl Med 44:870–876PubMedGoogle Scholar
  49. Kish SJ, Tong J, Hornykiewicz O, Rajput A, Chang LJ, Guttman M, Furukawa Y (2008) Preferential loss of serotonin markers in caudate versus putamen in Parkinson’s disease. Brain J Neurol 131:120–131Google Scholar
  50. Langston JW, Forno LS, Rebert CS, Irwin I (1984) Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey. Brain Res 292:390–394CrossRefPubMedGoogle Scholar
  51. Lavoie B, Parent A (1990) Immunohistochemical study of the serotoninergic innervation of the basal ganglia in the squirrel monkey. J Comp Neurol 299:1–16. doi: 10.1002/cne.902990102 CrossRefPubMedGoogle Scholar
  52. Lopez A, Munoz A, Guerra MJ, Labandeira-Garcia JL (2001) Mechanisms of the effects of exogenous levodopa on the dopamine-denervated striatum. Neuroscience 103:639–651CrossRefPubMedGoogle Scholar
  53. Maeda T, Kannari K, Shen H, Arai A, Tomiyama M, Matsunaga M, Suda T (2003) Rapid induction of serotonergic hyperinnervation in the adult rat striatum with extensive dopaminergic denervation. Neurosci Lett 343:17–20. doi:S0304394003002957 [pii]Google Scholar
  54. Maeda T, Nagata K, Yoshida Y, Kannari K (2005) Serotonergic hyperinnervation into the dopaminergic denervated striatum compensates for dopamine conversion from exogenously administered l-DOPA. Brain Res 1046:230–233. doi: 10.1016/j.brainres.2005.04.019 CrossRefPubMedGoogle Scholar
  55. Mann DM, Yates PO (1983) Pathological basis for neurotransmitter changes in Parkinson’s disease. Neuropathol Appl Neurobiol 9:3–19CrossRefPubMedGoogle Scholar
  56. Mathur BN, Capik NA, Alvarez VA, Lovinger DM (2011) Serotonin induces long-term depression at corticostriatal synapses. J Neurosci Off J Soc Neurosci 31:7402–7411. doi: 10.1523/JNEUROSCI.6250-10.201131/20/7402 CrossRefGoogle Scholar
  57. Michelsen KA, Prickaerts J, Steinbusch HW (2008) The dorsal raphe nucleus and serotonin: implications for neuroplasticity linked to major depression and Alzheimer’s disease. Prog Brain Res 172:233–264. doi: 10.1016/S0079-6123(08)00912-6 CrossRefPubMedGoogle Scholar
  58. Miyawaki E, Meah Y, Koller WC (1997) Serotonin, dopamine, and motor effects in Parkinson’s disease. Clin Neuropharmacol 20:300–310CrossRefPubMedGoogle Scholar
  59. Mori S, Ueda S, Yamada H, Takino T, Sano Y (1985) Immunohistochemical demonstration of serotonin nerve fibers in the corpus striatum of the rat, cat and monkey. Anat Embryol (Berl) 173:1–5CrossRefGoogle Scholar
  60. Mouton PR, Gokhale AM, Ward NL, West MJ (2002) Stereological length estimation using spherical probes. J Microsc 206:54–64. doi:1006 [pii]Google Scholar
  61. Navailles S, Bioulac B, Gross C, De Deurwaerdere P (2010) Serotonergic neurons mediate ectopic release of dopamine induced by L-DOPA in a rat model of Parkinson’s disease. Neurobiol Dis 38:136–143. doi: 10.1016/j.nbd.2010.01.012 CrossRefPubMedGoogle Scholar
  62. Navailles S, Bioulac B, Gross C, De Deurwaerdere P (2011) Chronic L-DOPA therapy alters central serotonergic function and L-DOPA-induced dopamine release in a region-dependent manner in a rat model of Parkinson’s disease. Neurobiol Dis 41:585–590. doi: 10.1016/j.nbd.2010.11.007 CrossRefPubMedGoogle Scholar
  63. Ng KY, Chase TN, Colburn RW, Kopin IJ (1970) L-Dopa-induced release of cerebral monoamines. Science 170:76–77CrossRefPubMedGoogle Scholar
  64. Ng KY, Colburn RW, Kopin IJ (1971) Effects of L-dopa on efflux of cerebral monoamines from synaptosomes. Nature 230:331–332CrossRefPubMedGoogle Scholar
  65. Obeso JA, Olanow CW, Nutt JG (2000) Levodopa motor complications in Parkinson’s disease. Trends Neurosci 23:S2–S7CrossRefPubMedGoogle Scholar
  66. Parent A, Hazrati LN (1995) Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop. Brain Res Brain Res Rev 20:91–127. doi:016501739400007C [pii]Google Scholar
  67. Parent M, Wallman MJ, Descarries L (2010) Distribution and ultrastructural features of the serotonin innervation in rat and squirrel monkey subthalamic nucleus. Eur J Neurosci 31:1233–1242. doi: 10.1111/j.1460-9568.2010.07143.x CrossRefPubMedGoogle Scholar
  68. Parent M, Wallman MJ, Gagnon D, Parent A (2011) Serotonin innervation of basal ganglia in monkeys and humans. J Chem Neuroanat 41:256–265. doi: 10.1016/j.jchemneu.2011.04.005S0891-0618(11)00048-2 CrossRefPubMedGoogle Scholar
  69. Pasik T, Pasik P (1982) Serotoninergic afferents in the monkey neostriatum. Acta Biol Acad Sci Hung 33:277–288PubMedGoogle Scholar
  70. Pasik P, Pasik T, Saavedra JP (1982) Immunocytochemical localization of serotonin at the ultrastructural level. J Histochem Cytochem 30:760–764CrossRefPubMedGoogle Scholar
  71. Paulus W, Jellinger K (1991) The neuropathologic basis of different clinical subgroups of Parkinson’s disease. J Neuropathol Exp Neurol 50:743–755CrossRefPubMedGoogle Scholar
  72. Perez-Otano I, Herrero MT, Oset C, De Ceballos ML, Luquin MR, Obeso JA, Del Rio J (1991) Extensive loss of brain dopamine and serotonin induced by chronic administration of MPTP in the marmoset. Brain Res 567:127–132. doi:0006-8993(91)91444-6 [pii]Google Scholar
  73. Pifl C, Schingnitz G, Hornykiewicz O (1991) Effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on the regional distribution of brain monoamines in the rhesus monkey. Neuroscience 44:591–605. doi:0306-4522(91)90080-8 [pii]Google Scholar
  74. Politis M, Wu K, Loane C, Kiferle L, Molloy S, Brooks DJ, Piccini P (2010) Staging of serotonergic dysfunction in Parkinson’s disease: an in vivo 11C-DASB PET study. Neurobiol Dis 40:216–221. doi: 10.1016/j.nbd.2010.05.028 CrossRefPubMedGoogle Scholar
  75. Politis M, Wu K, Loane C, Brooks DJ, Kiferle L, Turkheimer FE, Bain P, Molloy S, Piccini P (2014) Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients. J Clin Investig 124:1340–1349. doi: 10.1172/JCI71640 CrossRefPubMedPubMedCentralGoogle Scholar
  76. Raisman R, Cash R, Agid Y (1986) Parkinson’s disease: decreased density of 3H-imipramine and 3H-paroxetine binding sites in putamen. Neurology 36:556–560CrossRefPubMedGoogle Scholar
  77. Rajput AH, Fenton ME, Birdi S, Macaulay R, George D, Rozdilsky B, Ang LC, Senthilselvan A, Hornykiewicz O (2002) Clinical-pathological study of levodopa complications. Mov Disord Off J Mov Disord Soc 17:289–296CrossRefGoogle Scholar
  78. Riad M, Garcia S, Watkins KC, Jodoin N, Doucet E, Langlois X, el Mestikawy S, Hamon M, Descarries L (2000) Somatodendritic localization of 5-HT1A and preterminal axonal localization of 5-HT1B serotonin receptors in adult rat brain. J Comp Neurol 417:181–194. doi: 10.1002/(SICI)1096-9861(20000207)417:2<181:AID-CNE4>3.0.CO;2-A CrossRefPubMedGoogle Scholar
  79. Riahi G, Morissette M, Parent M, Di Paolo T (2011) Brain 5-HT(2A) receptors in MPTP monkeys and levodopa-induced dyskinesias. Eur J Neurosci 33:1823–1831. doi: 10.1111/j.1460-9568.2011.07675.x CrossRefPubMedGoogle Scholar
  80. Rozas G, Liste I, Guerra MJ, Labandeira-Garcia JL (1998) Sprouting of the serotonergic afferents into striatum after selective lesion of the dopaminergic system by MPTP in adult mice. Neurosci Lett 245:151–154CrossRefPubMedGoogle Scholar
  81. Russ H, Mihatsch W, Gerlach M, Riederer P, Przuntek H (1991) Neurochemical and behavioural features induced by chronic low dose treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the common marmoset: implications for Parkinson’s disease? Neurosci Lett 123:115–118. doi:0304-3940(91)90171-O [pii]Google Scholar
  82. Rylander D, Parent M, O’Sullivan SS, Dovero S, Lees AJ, Bezard E, Descarries L, Cenci MA (2010) Maladaptive plasticity of serotonin axon terminals in levodopa-induced dyskinesia. Ann Neurol 68:619–628. doi: 10.1002/ana.22097 CrossRefPubMedGoogle Scholar
  83. Scatton B, Javoy-Agid F, Rouquier L, Dubois B, Agid Y (1983) Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in Parkinson’s disease. Brain Res 275:321–328CrossRefPubMedGoogle Scholar
  84. Schneider JS (1990) Chronic exposure to low doses of MPTP. II. Neurochemical and pathological consequences in cognitively-impaired, motor asymptomatic monkeys. Brain Res 534:25–36. doi:0006-8993(90)90108-N [pii]Google Scholar
  85. Smits SM, Noorlander CW, Kas MJ, Ramakers GM, Smidt MP (2008) Alterations in serotonin signalling are involved in the hyperactivity of Pitx3-deficient mice. Eur J Neurosci 27:388–395. doi: 10.1111/j.1460-9568.2008.06032.x CrossRefPubMedGoogle Scholar
  86. Soghomonian JJ, Descarries L, Watkins KC (1989) Serotonin innervation in adult rat neostriatum. II. Ultrastructural features: a radioautographic and immunocytochemical study. Brain Res 481:67–86. doi:0006-8993(89)90486-1 [pii]Google Scholar
  87. Strecker K, Wegner F, Hesse S, Becker GA, Patt M, Meyer PM, Lobsien D, Schwarz J, Sabri O (2011) Preserved serotonin transporter binding in de novo Parkinson’s disease: negative correlation with the dopamine transporter. J Neurol 258:19–26. doi: 10.1007/s00415-010-5666-5 CrossRefPubMedGoogle Scholar
  88. Tahar AH, Gregoire L, Darre A, Belanger N, Meltzer L, Bedard PJ (2004) Effect of a selective glutamate antagonist on L-dopa-induced dyskinesias in drug-naive parkinsonian monkeys. Neurobiol Dis 15:171–176. doi: 10.1016/j.nbd.2003.10.007 CrossRefGoogle Scholar
  89. Tanaka H, Kannari K, Maeda T, Tomiyama M, Suda T, Matsunaga M (1999) Role of serotonergic neurons in L-DOPA-derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats. NeuroReport 10:631–634CrossRefPubMedGoogle Scholar
  90. Tassone A, Madeo G, Schirinzi T, Vita D, Puglisi F, Ponterio G, Borsini F, Pisani A, Bonsi P (2011) Activation of 5-HT6 receptors inhibits corticostriatal glutamatergic transmission. Neuropharmacology 61:632–637. doi: 10.1016/j.neuropharm.2011.05.004 CrossRefPubMedGoogle Scholar
  91. Umbriaco D, Watkins KC, Descarries L, Cozzari C, Hartman BK (1994) Ultrastructural and morphometric features of the acetylcholine innervation in adult rat parietal cortex: an electron microscopic study in serial sections. J Comp Neurol 348:351–373. doi: 10.1002/cne.903480304 CrossRefPubMedGoogle Scholar
  92. Van Bockstaele EJ, Pickel VM (1993) Ultrastructure of serotonin-immunoreactive terminals in the core and shell of the rat nucleus accumbens: cellular substrates for interactions with catecholamine afferents. J Comp Neurol 334:603–617. doi: 10.1002/cne.903340408 CrossRefPubMedGoogle Scholar
  93. Van Bockstaele EJ, Chan J, Pickel VM (1996) Pre- and postsynaptic sites for serotonin modulation of GABA-containing neurons in the shell region of the rat nucleus accumbens. J Comp Neurol 371:116–128. doi: 10.1002/(SICI)1096-9861(19960715)371:1<116:AID-CNE7>3.0.CO;2-6 CrossRefPubMedGoogle Scholar
  94. Wallman MJ, Gagnon D, Parent M (2011) Serotonin innervation of human basal ganglia. Eur J Neurosci 33:1519–1532. doi: 10.1111/j.1460-9568.2011.07621.x CrossRefPubMedGoogle Scholar
  95. Yahr MD (1972) The treatment of parkinsonism. Current concepts. Med Clin N Am 56:1377–1392CrossRefPubMedGoogle Scholar
  96. Yamazoe I, Takeuchi Y, Matsushita H, Kawano H, Sawada T (2001) Serotonergic heterotypic sprouting in the unilaterally dopamine-depleted mouse neostriatum. Dev Neurosci 23:78–83. doi:48698Google Scholar
  97. Zeng BY, Iravani MM, Jackson MJ, Rose S, Parent A, Jenner P (2010) Morphological changes in serotoninergic neurites in the striatum and globus pallidus in levodopa primed MPTP treated common marmosets with dyskinesia. Neurobiol Dis 40:599–607. doi: 10.1016/j.nbd.2010.08.004S0969-9961(10)00256-1 CrossRefPubMedGoogle Scholar
  98. Zhou FC, Bledsoe S, Murphy J (1991) Serotonergic sprouting is induced by dopamine-lesion in substantia nigra of adult rat brain. Brain Res 556:108–116. doi:0006-8993(91)90553-8 [pii]Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • D. Gagnon
    • 1
  • L. Gregoire
    • 2
  • T. Di Paolo
    • 2
  • Martin Parent
    • 1
    Email author
  1. 1.Department of Psychiatry and Neuroscience, Faculty of medicineCentre de recherche de l’Institut universitaire en santé mentale de Québec, Université LavalQuebec CityCanada
  2. 2.Faculty of PharmacyCentre de recherche du CHU de Québec, Université LavalQuebec CityCanada

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