L-DOPA-induced dyskinesias (LIDs) are one of the main motor side effects of L-DOPA therapy in Parkinson's disease. The review will consider the biochemical evidence indicating that the serotonergic neurons are involved in the dopaminergic effects of L-DOPA in the brain. The consequences are an ectopic and aberrant release of dopamine that follows the serotonergic innervation of the brain. After mid- to long-term treatment with L-DOPA, the pattern of L-DOPA-induced dopamine release is modified. In several brain regions, its effect is dramatically reduced while, in the striatum, its effect is quite preserved. LIDs could appear when the dopaminergic effects of L-DOPA fall in brain areas such as the cortex, enhancing the subcortical impact of dopamine and promoting aberrant motor responses. The consideration of the serotonergic system in the core mechanism of action of L-DOPA opens an important reserve of possible strategies to limit LIDs. 1. Introduction Parkinson’s disease is the second most devastating neurodegenerative disease affecting more than 6 million people worldwide and whose prevalence is expected to double within the next twenty years [1]. This neurological disorder is characterized by the progressive loss of mesencephalic dopaminergic (DA) neurons from the substantia nigra pars compacta and associated with numerous motor symptoms (bradykinesia, rigidity, and tremor) [2, 3]. L-DOPA, the precursor of DA, has been introduced in the mid 60’s as a miracle pill to prevent the motor symptoms [4, 5]. However, upon chronic use of this medication, its efficacy slowly decreases leading to increase the doses of L-DOPA, which generate numerous side effects. After 5 to 10 years of L-DOPA treatment, Parkinsonian patients develop dyskinesias [6], which consist of stereotypical choreic or ballistic movements involving mostly the head, trunk, and limbs [7]. These abnormal involuntary movements are often more debilitating than the motor symptoms themselves. Preclinical research has permitted validating animal models to study the mechanisms of L-DOPA-induced dyskinesias (LIDs). The most commonly used rat model that shows best face and predictive validity, has been developed by Cenci and collaborators [8, 9] by producing severe lesion of the nigrostriatal DA pathway in adult rats with the unilateral injection of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle [10, 11]. A chronic treatment with L-DOPA for 3 weeks at low therapeutic doses (6–10？mg/kg) induced axial, limb, and orolingual abnormal involuntary movements (ALO AIMs) of variable occurrence and
References
[1]
E. R. Dorsey, R. Constantinescu, J. P. Thompson et al., “Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030,” Neurology, vol. 68, no. 5, pp. 384–386, 2007.
[2]
O. Hornykiewicz, “Dopamine (3-hydroxytyramine) and brain function,” Pharmacological Reviews, vol. 18, no. 2, pp. 925–964, 1966.
[3]
H. Bernheimer, W. Birkmayer, O. Hornykiewicz, K. Jellinger, and F. Seitelberger, “Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations,” Journal of the Neurological Sciences, vol. 20, no. 4, pp. 415–455, 1973.
[4]
G. C. Cotzias, “L-Dopa for Parkinsonism,” New England Journal of Medicine, vol. 278, no. 11, p. 630, 1968.
[5]
O. Hornykiewicz, “Dopamine in the basal ganglia. Its role and therapeutic implications (including the clinical use of L-DOPA),” British Medical Bulletin, vol. 29, no. 2, pp. 172–178, 1973.
[6]
J. E. Ahlskog and M. D. Muenter, “Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature,” Movement Disorders, vol. 16, no. 3, pp. 448–458, 2001.
[7]
J. Jankovic, “Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations,” Movement Disorders, vol. 20, no. 11, pp. S11–S16, 2005.
[8]
M. Lundblad, M. Andersson, C. Winkler, D. Kirik, N. Wierup, and M. A. Cenci Nilsson, “Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson's disease,” European Journal of Neuroscience, vol. 15, no. 1, pp. 120–132, 2002.
[9]
M. A. Cenci and K. E. Ohlin, “Rodent models of treatment-induced motor complications in Parkinson's disease,” Parkinsonism and Related Disorders, vol. 15, supplement 4, pp. S13–S17, 2009.
[10]
U. Ungerstedt, “6-hydroxy-dopamine induced degeneration of central monoamine neurons,” European Journal of Pharmacology, vol. 5, no. 1, pp. 107–110, 1968.
[11]
M. Olsson, G. Nikkhah, C. Bentlage, and A. Bjorklund, “Forelimb akinesia in the rat Parkinson model: differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test,” Journal of Neuroscience, vol. 15, no. 5, pp. 3863–3875, 1995.
[12]
M. A. Cenci, “L-DOPA-induced dyskinesia: cellular mechanisms and approaches to treatment,” Parkinsonism and Related Disorders, vol. 13, no. 3, pp. S263–S267, 2007.
[13]
U. Ungerstedt, “Postsynaptic supersensitivity after 6-hydroxy-dopamine induced degeneration of the nigro-striatal dopamine system,” Acta Physiologica Scandinavica, vol. 367, supplement, pp. 69–93, 1971.
[14]
U. Ungerstedt, “Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behaviour,” Acta Physiologica Scandinavica, vol. 367, supplement, pp. 49–68, 1971.
[15]
T. Zetterstrom, M. Herrera-Marschitz, and U. Ungerstedt, “Simultaneous measurement of dopamine release and rotational behaviour in 6-hydroxydopamine denervated rats using intracerebral dialysis,” Brain Research, vol. 376, no. 1, pp. 1–7, 1986.
[16]
B. S. Bunney, G. K. Aghajanian, and R. H. Roth, “Comparison of effects of L dopa amphetamine and apomorphine on firing rate of rat dopaminergic neurones,” Nature New Biology, vol. 245, no. 143, pp. 123–125, 1973.
[17]
N. B. Mercuri, P. Calabresi, and G. Bernardi, “Responses of rat substantia nigra compacta neurones to L-DOPA,” British Journal of Pharmacology, vol. 100, no. 2, pp. 257–260, 1990.
[18]
D. G. Harden and A. A. Grace, “Activation of dopamine cell firing by repeated L-DOPA administration to dopamine-depleted rats: its potential role in mediating the therapeutic response to L-DOPA treatment,” Journal of Neuroscience, vol. 15, no. 9, pp. 6157–6166, 1995.
[19]
T. Maeda, K. Kannari, T. Suda, and M. Matsunaga, “Loss of regulation by presynaptic dopamine D2 receptors of exogenous L- DOPA-derived dopamine release in the dopaminergic denervated striatum,” Brain Research, vol. 817, no. 1-2, pp. 185–191, 1999.
[20]
D. W. Miller and E. D. Abercrombie, “Role of high-affinity dopamine uptake and impulse activity in the appearance of extracellular dopamine in striatum after administration of exogenous L-DOPA: studies in intact and 6-hydroxydopamine-treated rats,” Journal of Neurochemistry, vol. 72, no. 4, pp. 1516–1522, 1999.
[21]
S. Sarre, N. De Klippel, P. Herregodts, G. Ebinger, and Y. Michotte, “Biotransformation of locally applied L-dopa in the corpus striatum of the hemi-Parkinsonian rat studied with microdialysis,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 350, no. 1, pp. 15–21, 1994.
[22]
K. Kannari, H. Tanaka, T. Maeda, M. Tomiyama, T. Suda, and M. Matsunaga, “Reserpine pretreatment prevents increases in extracellular striatal dopamine following L-DOPA administration in rats with nigrostriatal denervation,” Journal of Neurochemistry, vol. 74, no. 1, pp. 263–269, 2000.
[23]
W. Y. Lee, J. W. Chang, N. L. Nemeth, and U. J. Kang, “Vesicular monoamine transporter-2 and aromatic l-amino acid decarboxylase enhance dopamine delivery after L-3,4-dihydroxyphenylalanine administration in parkinsonian rats,” Journal of Neuroscience, vol. 19, no. 8, pp. 3266–3274, 1999.
[24]
S. Navailles, M. Carta, M. Guthrie, and P. De Deurwaerdere, “L-DOPA and serotonergic neurons: functional implication and therapeutic perspectives in Parkinson’s disease,” Central Nervous System Agents in Medicinal Chemistry. In press.
[25]
L. K. Ng, T. N. Chase, R. W. Colburn, and I. J. Kopin, “l-dopa-induced release of cerebral monoamines,” Science, vol. 170, no. 953, pp. 76–77, 1970.
[26]
F. Tison, N. Mons, M. Geffard, and P. Henry, “The metabolism of exogenous L-Dopa in the brain: an immunohistochemical study of its conversion to dopamine in non-catecholaminergic cells of the rat brain,” Journal of Neural Transmission, vol. 3, no. 1, pp. 27–39, 1991.
[27]
R. Arai, N. Karasawa, M. Geffard, and I. Nagatsu, “L-DOPA is converted to dopamine in serotonergic fibers of the striatum of the rat: a double-labeling immunofluorescence study,” Neuroscience Letters, vol. 195, no. 3, pp. 195–198, 1995.
[28]
H. Yamada, Y. Aimi, I. Nagatsu, K. Taki, M. Kudo, and R. Arai, “Immunohistochemical detection of l-DOPA-derived dopamine within serotonergic fibers in the striatum and the substantia nigra pars reticulata in Parkinsonian model rats,” Neuroscience Research, vol. 59, no. 1, pp. 1–7, 2007.
[29]
L. K. Ng, R. W. Colburn, and I. J. Kopin, “Effects of L-dopa on accumulation and efflux of monoamines in particles of rat brain homogenates,” Journal of Pharmacology and Experimental Therapeutics, vol. 183, no. 2, pp. 316–325, 1972.
[30]
L. K. Ng, T. N. Chase, R. W. Colburn, and I. J. Kopin, “L-dopa in Parkinsonism. A possible mechanism of action,” Neurology, vol. 22, no. 7, pp. 688–696, 1972.
[31]
S. Navailles, B. Bioulac, C. Gross, and P. De Deurwaerdère, “Serotonergic neurons mediate ectopic release of dopamine induced by l-DOPA in a rat model of Parkinson's disease,” Neurobiology of Disease, vol. 38, no. 1, pp. 136–143, 2010.
[32]
H. Tanaka, K. Kannari, T. Maeda, M. Tomiyama, T. Suda, and M. Matsunaga, “Role of serotonergic neuron in L-DOPA-derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats,” NeuroReport, vol. 10, no. 3, pp. 631–634, 1999.
[33]
K. Kannari, H. Yamato, H. Shen, M. Tomiyama, T. Suda, and M. Matsunaga, “Activation of 5-HT1A but not 5-HT1B receptors attenuates an increase in extracellular dopamine derived from exogenously administered L-DOPA in the striatum with nigrostriatal denervation,” Journal of Neurochemistry, vol. 76, no. 5, pp. 1346–1353, 2001.
[34]
H. Yamato, K. Kannari, H. Shen, T. Suda, and M. Matsunaga, “Fluoxetine reduces L-DOPA-derived extracellular DA in the 6-OHDA-lesioned rat striatum,” NeuroReport, vol. 12, no. 6, pp. 1123–1126, 2001.
[35]
J. S. Sprouse and G. K. Aghajanian, “Electrophysiological responses of serotonergic dorsal raphe enurons to 5-HT1A and 5-HT1B agonists,” Synapse, vol. 1, no. 1, pp. 3–9, 1987.
[36]
F. J. Bosker, T. Y. C. E. De Winter, A. A. Klompmakers, and H. G. M. Westenberg, “Flesinoxan dose-dependently reduces extracellular 5-hydroxytryptamine (5-HT) in rat median raphe and dorsal hippocampus through activation of 5-HT1A receptors,” Journal of Neurochemistry, vol. 66, no. 6, pp. 2546–2555, 1996.
[37]
D. A. Knobelman, H. F. Kung, and I. Lucki, “Regulation of extracellular concentrations of 5-hydroxytryptamine (5- HT)in mouse striatum by 5-HT(1A) and 5-HT(1B) receptors,” Journal of Pharmacology and Experimental Therapeutics, vol. 292, no. 3, pp. 1111–1117, 2000.
[38]
M. Riad, S. Garcia, K. C. Watkins et al., “Somatodendritic localization of 5-HT1A and preterminal axonal localization of 5-HT1B serotonin receptors in adult rat brain,” Journal of Comparative Neurology, vol. 417, no. 2, pp. 181–194, 2000.
[39]
T. Sharp, S. R. Bramwell, S. Hjorth, and D. G. Grahame-Smith, “Pharmacological characterization of 8-OH-DPAT-induced inhibition of rat hippocampal 5-HT release in vivo as measured by microdialysis,” British Journal of Pharmacology, vol. 98, no. 3, pp. 989–997, 1989.
[40]
A. Adell, A. Carceller, and F. Artigas, “In vivo brain dialysis study of the somatodendritic release of serotonin in the raphe nuclei of the rat: effects of 8-hydroxy-2-(di-n- propylamino)tetralin,” Journal of Neurochemistry, vol. 60, no. 5, pp. 1673–1681, 1993.
[41]
J. M. Casanovas and F. Artigas, “Differential effects of ipsapirone on 5-hydroxytryptamine release in the dorsal and median raphe neuronal pathways,” Journal of Neurochemistry, vol. 67, no. 5, pp. 1945–1952, 1996.
[42]
L. Arborelius, G. G. Nomikos, P. Grillner et al., “5-HT(1A) receptor antagonists increase the activity of serotonergic cells in the dorsal raphe nucleus in rats treated acutely or chronically with citalopram,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 352, no. 2, pp. 157–165, 1995.
[43]
Y. Temel, L. J. Boothman, A. Blokland et al., “Inhibition of 5-HT neuron activity and induction of depressive-like behavior by high-frequency stimulation of the subthalamic nucleus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 43, pp. 17087–17092, 2007.
[44]
S. Navailles, A. Benazzouz, B. Bioulac, C. Gross, and P. De Deurwaerdère, “High-frequency stimulation of the subthalamic nucleus and L-3,4-dihydroxyphenylalanine inhibit in vivo serotonin release in the prefrontal cortex and hippocampus in a rat model of Parkinson's disease,” Journal of Neuroscience, vol. 30, no. 6, pp. 2356–2364, 2010.
[45]
S. Navailles, B. Bioulac, C. Gross, and P. De Deurwaerdère, “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,” Neurobiology of Disease, vol. 41, no. 2, pp. 585–590, 2011.
[46]
E. C. Azmitia and M. Segal, “An autoradiographic analysis of the different ascending projections of the dorsal and median raphe nuclei in the rat,” Journal of Comparative Neurology, vol. 179, no. 3, pp. 641–667, 1978.
[47]
H. W. Steinbusch, “Serotonin-immunoreactive neurons and their projections in the CNS,” in Handbook of Chemical Neuroanatomy—Classical Transmitters and Transmitters Receptors in the CNS Part II, A. Bj？rklund, T. H？kfelt, and M. J. Kuhar, Eds., pp. 68–125, Amsterdam,The Netherlands, 1984.
[48]
H. S. Lindgren, D. R. Andersson, S. Lagerkvist, H. Nissbrandt, and M. A. Cenci, “L-DOPA-induced dopamine efflux in the striatum and the substantia nigra in a rat model of Parkinson's disease: temporal and quantitative relationship to the expression of dyskinesia,” Journal of Neurochemistry, vol. 112, no. 6, pp. 1465–1476, 2010.
[49]
J. A. Obeso, C. Marin, C. Rodriguez-Oroz et al., “The basal ganglia in Parkinson's disease: current concepts and unexplained observations,” Annals of Neurology, vol. 64, no. 2, pp. S30–S46, 2008.
[50]
P. Seeman, “Brain dopamine receptors,” Pharmacological Reviews, vol. 32, no. 3, pp. 229–313, 1980.
[51]
W. D. Brown, M. D. Taylor, A. D. Roberts et al., “FluoroDOPA PET shows the nondopaminergic as well as dopaminergic destinations of levodopa,” Neurology, vol. 53, no. 6, pp. 1212–1218, 1999.
[52]
R. M. Kostrzewa, “Dopamine receptor supersensitivity,” Neuroscience and Biobehavioral Reviews, vol. 19, no. 1, pp. 1–17, 1995.
[53]
J. Tong, P. S. Fitzmaurice, L. C. Ang, Y. Furukawa, M. Guttman, and S. J. Kish, “Brain dopamine-stimulated adenylyl cyclase activity in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy,” Annals of Neurology, vol. 55, no. 1, pp. 125–129, 2004.
[54]
M. R. Ahmed, A. Berthet, E. Bychkov et al., “Lentiviral overexpression of GRK6 alleviates L-Dopa-induced dyskinesia in experimental parkinson's disease,” Science Translational Medicine, vol. 2, no. 28, pp. 28–ra28, 2010.
[55]
D. Rylander, M. Parent, S. S. O-Sullivan et al., “Maladaptive plasticity of serotonin axon terminals in levodopa-induced dyskinesia,” Annals of Neurology, vol. 68, no. 5, pp. 619–628, 2010.
[56]
B. Y. Zeng, M. M. Iravani, M. J. Jackson, S. Rose, A. Parent, and P. Jenner, “Morphological changes in serotoninergic neurites in the striatum and globus pallidus in levodopa primed MPTP treated common marmosets with dyskinesia,” Neurobiology of Disease, vol. 40, no. 3, pp. 599–607, 2010.
[57]
T. N. Chase, “Levodopa therapy: consequences of the nonphysiologic replacement of dopamine,” Neurology, vol. 50, supplement 5, pp. S17–S25, 1998.
[58]
C. W. Olanow and J. A. Obeso, “Pulsatile stimulation of dopamine receptors and levodopa-induced motor complications in Parkinson's disease: implications for the early use of COMT inhibitors,” Neurology, vol. 55, supplement 4, no. 11, pp. S72–SS77, 2000.
[59]
R. De La Fuente-Fernández, V. Sossi, Z. Huang et al., “Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson's disease: implications for dyskinesias,” Brain, vol. 127, no. 12, pp. 2747–2754, 2004.
[60]
M. A. Cenci and M. Lundblad, “Post- versus presynaptic plasticity in L-DOPA-induced dyskinesia,” Journal of Neurochemistry, vol. 99, no. 2, pp. 381–392, 2006.
[61]
M. Carta, T. Carlsson, D. Kirik, and A. Bj？rklund, “Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats,” Brain, vol. 130, no. 7, pp. 1819–1833, 2007.
[62]
M. Carta, T. Carlsson, A. Mu？oz, D. Kirik, and A. Bj？rklund, “Serotonin-dopamine interaction in the induction and maintenance of L-DOPA-induced dyskinesias,” Progress in Brain Research, vol. 172, pp. 465–478, 2008.
[63]
A. Ulusoy, G. Sahin, and D. Kirik, “Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA-induced dyskinesia in rats,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 29, pp. 13159–13164, 2010.
[64]
A. Mu？oz, T. Carlsson, E. Tronci, D. Kirik, A. Bj？rklund, and M. Carta, “Serotonin neuron-dependent and -independent reduction of dyskinesia by 5-HT1A and 5-HT1B receptor agonists in the rat Parkinson model,” Experimental Neurology, vol. 219, no. 1, pp. 298–307, 2009.
[65]
C. Marin, E. Aguilar, M. C. Rodríguez-Oroz, G. D. Bartoszyk, and J. A. Obeso, “Local administration of sarizotan into the subthalamic nucleus attenuates levodopa-induced dyskinesias in 6-OHDA-lesioned rats,” Psychopharmacology, vol. 204, no. 2, pp. 241–250, 2009.
[66]
S. Sarre, P. Herregodts, D. Deleu et al., “Biotransformation of L-DOPA in striatum and substantia nigra of rats with a unilateral, nigrostriatal lesion: a microdialysis study,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 346, no. 3, pp. 277–285, 1992.
[67]
S. Sarre, I. Smolders, K. Thorré, G. Ebinger, and Y. Michotte, “Biotransformation of locally applied precursors of dopamine, serotonin and noradrenaline in striatum and hippocampus: a microdialysis study,” Journal of Neural Transmission, vol. 104, no. 11-12, pp. 1215–1228, 1997.
[68]
D. Orosz and J. P. Bennett, “Simultaneous microdialysis in striatum and substantia nigra suggests that the nigra is a major site of action of L-dihydroxyphenylalanine in the “hemiparkinsonian” rat,” Experimental Neurology, vol. 115, no. 3, pp. 388–393, 1992.
[69]
V. Di Matteo, M. Pierucci, E. Esposito, G. Crescimanno, A. Benigno, and G. Di Giovanni, “Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders,” Progress in Brain Research, vol. 172, pp. 423–463, 2008.
[70]
D. B. Putterman, A. C. Munhall, L. B. Kozell, J. K. Belknap, and S. W. Johnson, “Evaluation of levodopa dose and magnitude of dopamine depletion as risk factors for levodopa-induced dyskinesia in a rat model of Parkinson's disease,” Journal of Pharmacology and Experimental Therapeutics, vol. 323, no. 1, pp. 277–284, 2007.
[71]
K. Thorré, S. Sarre, I. Smolders, G. Ebinger, and Y. Michotte, “Dopaminergic regulation of serotonin release in the substantia nigra of the freely moving rat using microdialysis,” Brain Research, vol. 796, no. 1-2, pp. 107–116, 1998.
[72]
S. J. Gil, C. H. Park, J. E. Lee, Y. K. Minn, and H. C. Koh, “Positive association between striatal serotonin level and abnormal involuntary movements in chronic l-DOPA-treated hemiparkinsonian rats,” Brain Research Bulletin, vol. 96, no. 6, pp. 1718–1727, 2011.
[73]
M. Lundblad, S. Af Bjerkén, M. A. Cenci, F. Pomerleau, G. A. Gerhardt, and I. Str？mberg, “Chronic intermittent L-DOPA treatment induces changes in dopamine release,” Journal of Neurochemistry, vol. 108, no. 4, pp. 998–1008, 2009.
[74]
S. Gil, C. Park, J. Lee, and H. Koh, “The roles of striatal serotonin and l-amino-acid decarboxylase on l-DOPA-induced dyskinesia in a hemiparkinsonian rat model,” Cellular and Molecular Neurobiology, vol. 30, no. 6, pp. 817–825, 2010.
[75]
X. Zhang, P. E. Andren, P. Greengard, and P. Svenningsson, “Evidence for a role of the 5-HT1B receptor and its adaptor protein, p11, in L-DOPA treatment of an animal model of Parkinsonism,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 6, pp. 2163–2168, 2008.
[76]
X. Zhang, P. E. Andren, and P. Svenningsson, “Changes on 5-HT2 receptor mRNAs in striatum and subthalamic nucleus in Parkinson's disease model,” Physiology and Behavior, vol. 92, no. 1-2, pp. 29–33, 2007.
[77]
P. Huot, T. H. Johnston, J. B. Koprich, L. Winkelmolen, S. H. Fox, and J. M. Brotchie, “Regulation of cortical and striatal 5-HT(1A) receptors in the MPTP-lesioned macaque,” Neurobiology of Aging. In press.
[78]
G. Riahi, M. Morissette, M. Parent, and T. Di Paolo, “Brain 5-HT2A receptors in MPTP monkeys and levodopa-induced dyskinesias,” European Journal of Neuroscience, vol. 33, no. 10, pp. 1823–1831, 2011.
[79]
S. L. Nicholson and J. M. Brotchie, “5-Hydroxytryptamine (5-HT, serotonin) and Parkinson's disease—opportunities for novel therapeutics to reduce the problems of levodopa therapy,” European Journal of Neurology, vol. 9, supplement 3, pp. 1–6, 2002.
[80]
S. H. Fox and J. M. Brotchie, “5-HT(2C) receptor binding is increased in the substantia Nigra pars reticulata in Parkinson's disease,” Movement Disorders, vol. 15, no. 6, pp. 1064–1069, 2000.
[81]
W. Meissner, P. Ravenscroft, R. Reese et al., “Increased slow oscillatory activity in substantia nigra pars reticulata triggers abnormal involuntary movements in the 6-OHDA-lesioned rat in the presence of excessive extracelullar striatal dopamine,” Neurobiology of Disease, vol. 22, no. 3, pp. 586–598, 2006.
[82]
S. H. Fox, R. Chuang, and J. M. Brotchie, “Serotonin and Parkinson's disease: on movement, mood, and madness,” Movement Disorders, vol. 24, no. 9, pp. 1255–1266, 2009.
[83]
B. Scholtissen, F. R. J. Verhey, J. J. Adam, W. Weber, and A. F. G. Leentjens, “Challenging the serotonergic system in Parkinson disease patients: effects on cognition, mood, and motor performance,” Clinical Neuropharmacology, vol. 29, no. 5, pp. 276–285, 2006.
[84]
M. Carta, H. S. Lindgren, M. Lundblad, R. Stancampiano, F. Fadda, and M. A. Cenci, “Role of striatal L-DOPA in the production of dyskinesia in 6-hydroxydopamine lesioned rats,” Journal of Neurochemistry, vol. 96, no. 6, pp. 1718–1727, 2006.
[85]
K. L. Eskow, K. B. Dupre, C. J. Barnum, S. O. Dickinson, J. Y. Park, and C. Bishop, “The role of the dorsal raphe nucleus in the development, expression, and treatment of L-dopa-induced dyskinesia in hemiparkinsonian rats,” Synapse, vol. 63, no. 7, pp. 610–620, 2009.
[86]
G. Bartholini, M. Da Prada, and A. Pletscher, “Decrease of cerebral 5-hydroxytryptamine by 3,4-dihydroxyphenylalanine after inhibition of extracerebral decarboxylase,” Journal of Pharmacy and Pharmacology, vol. 20, no. 3, pp. 228–229, 1968.
[87]
G. M. Everett and J. W. Borcherding, “L-dopa: effect on concentrations of dopamine, norepinephrine, and serotonin in brains of mice,” Science, vol. 168, no. 3933, pp. 849–850, 1970.
[88]
H. Tohgi, T. Abe, S. Takahashi, J. Takahashi, and H. Hamato, “Alterations in the concentration of serotonergic and dopaminergic substances in the cerebrospinal fluid of patients with Parkinson's disease, and their changes after L-dopa administration,” Neuroscience Letters, vol. 159, no. 1-2, pp. 135–138, 1993.
[89]
F. Hery, G. Simonnet, S. Bourgoin, et al., “Effect of nerve activity on the in vivo release of [3H]serotonin continuously formed from L-[3H]tryptophan in the caudate nucleus of the cat,” Brain Research, vol. 169, no. 2, pp. 317–334, 1979.
[90]
P. Blier, A. Serrano, and B. Scatton, “Differential responsiveness of the rat dorsal and median raphe 5-HT systems to 5-HT1 receptor agonists and p-chloroamphetamine,” Synapse, vol. 5, no. 2, pp. 120–133, 1990.
[91]
D. S. Kreiss and I. Lucki, “Differential regulation of serotonin (5-HT) release in the striatum and hippocampus by 5-HT(1A) autoreceptors of the dorsal and median raphe nuclei,” Journal of Pharmacology and Experimental Therapeutics, vol. 269, no. 3, pp. 1268–1279, 1994.
[92]
I. Hervás, N. Bel, A. G. Fernández, J. M. Palacios, and F. Artigas, “In vivo control of 5-hydroxytryptamine release by terminal autoreceptors in rat brain areas differentially innervated by the dorsal and median raphe nuclei,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 358, no. 3, pp. 315–322, 1998.
[93]
R. Invernizzi, M. Carli, A. Di Clemente, and R. Samanin, “Administration of 8-hydroxy-2-(di-n-propylamino)tetralin in raphe nuclei dorsalis and medianus reduces serotonin synthesis in the rat brain: differences in potency and regional sensitivity,” Journal of Neurochemistry, vol. 56, no. 1, pp. 243–247, 1991.
[94]
R. Invernizzi, C. Velasco, M. Bramante, A. Longo, and R. Samanin, “Effect of 5-HT(1A) receptor antagonists on citalopram-induced increase in extracellular serotonin in the frontal cortex, striatum and dorsal hippocampus,” Neuropharmacology, vol. 36, no. 4-5, pp. 467–473, 1997.
[95]
J. M. Casanovas, M. Lésourd, and F. Artigas, “The effect of the selective 5-HT(1A) agonists alnespirone (S-20499) and 8-OH-DPAT on extracellular 5-hydroxytryptamine in different regions of rat brain,” British Journal of Pharmacology, vol. 122, no. 4, pp. 733–741, 1997.
[96]
L. Romero and F. Artigas, “Preferential potentiation of the effects of serotonin uptake inhibitors by 5-HT(1A) receptor antagonists in the dorsal raphe pathway: role of somatodendritic autoreceptors,” Journal of Neurochemistry, vol. 68, no. 6, pp. 2593–2603, 1997.
[97]
B. Amilhon, E. Lepicard, T. Renoir et al., “VGLUT3 (vesicular glutamate transporter type 3) contribution to the regulation of serotonergic transmission and anxiety,” Journal of Neuroscience, vol. 30, no. 6, pp. 2198–2210, 2010.
[98]
R. McQuade and T. Sharp, “Functional mapping of dorsal and median raphe 5-hydroxytryptamine pathways in forebrain of the rat using microdialysis,” Journal of Neurochemistry, vol. 69, no. 2, pp. 791–796, 1997.
[99]
P. Gaspar, O. Cases, and L. Maroteaux, “The developmental role of serotonin: news from mouse molecular genetics,” Nature Reviews Neuroscience, vol. 4, no. 12, pp. 1002–1012, 2003.
[100]
V. Kiyasova, S. P. Fernandez, J. Laine et al., “A genetically defined morphologically and functionally unique subset of 5-HT neurons in the mouse raphe nuclei,” Journal of Neuroscience, vol. 31, no. 8, pp. 2756–2768, 2011.
[101]
B. Picconi, A. Pisani, I. Barone et al., “Pathological synaptic plasticity in the striatum: implications for parkinson's disease,” NeuroToxicology, vol. 26, no. 5, pp. 779–783, 2005.
[102]
B. Picconi, V. Ghiglieri, and P. Calabresi, “L-3,4-dihydroxyphenylalanine-induced sprouting of serotonin axon terminals: a useful biomarker for dyskinesias?” Annals of Neurology, vol. 68, no. 5, pp. 578–580, 2010.
[103]
I. A. Prescott, J. O. Dostrovsky, E. Moro, M. Hodaie, A. M. Lozano, and W. D. Hutchison, “Levodopa enhances synaptic plasticity in the substantia nigra pars reticulata of Parkinson's disease patients,” Brain, vol. 132, no. 2, pp. 309–318, 2009.
[104]
A. Berthet, G. Porras, E. Doudnikoff et al., “Pharmacological analysis demonstrates dramatic alteration of D1 dopamine receptor neuronal distribution in the rat analog of L-DOPA-induced dyskinesia,” Journal of Neuroscience, vol. 29, no. 15, pp. 4829–4835, 2009.
[105]
D. Frechilla, A. Cobreros, L. Saldise et al., “Serotonin 5-HT1A receptor expression is selectively enhanced in the striosomal compartment of chronic Parkinsonian monkeys,” Synapse, vol. 39, no. 4, pp. 288–296, 2001.
[106]
M. Doder, E. A. Rabiner, N. Turjanski, A. J. Lees, and D. J. Brooks, “Tremor in Parkinson's disease and serotonergic dysfunction: an 11C-WAY 100635 PET study,” Neurology, vol. 60, no. 4, pp. 601–605, 2003.
[107]
S. J. Kish, “Biochemistry of Parkinson's disease: is a brain serotonergic deficiency a characteristic of idiopathic Parkinson's disease?” Advances in Neurology, vol. 91, pp. 39–49, 2003.
[108]
B. Scholtissen, F. R. J. Verhey, H. W. M. Steinbusch, and A. F. G. Leentjens, “Serotonergic mechanisms in Parkinson's disease: opposing results from preclinical and clinical data,” Journal of Neural Transmission, vol. 113, no. 1, pp. 59–73, 2006.
[109]
K. A. Jellinger, “Pathology of Parkinson's disease: changes other than the nigrostriatal pathway,” Molecular and Chemical Neuropathology, vol. 14, no. 3, pp. 153–197, 1991.
[110]
G. M. Halliday, P. C. Blumbergs, R. G. H. Cotton, W. W. Blessing, and L. B. Geffen, “Loss of brainstem serotonin- and substance P-containing neurons in Parkinson's disease,” Brain Research, vol. 510, no. 1, pp. 104–107, 1990.
[111]
G. G. Kovacs, S. Kl？ppel, I. Fischer et al., “Nucleus-specific alteration of raphe neurons in human neurodegenerative disorders,” NeuroReport, vol. 14, no. 1, pp. 73–76, 2003.
[112]
C. P. L. H. Chen, J. T. Alder, L. Bray, A. E. Kingsbury, P. T. Francis, and O. J. F. Foster, “Post-synaptic 5-HT(1A) and 5-HT(2A) receptors are increased in Parkinson's disease neocortex,” Annals of the New York Academy of Sciences, vol. 861, pp. 288–289, 1998.
[113]
S. J. Kish, J. Tong, O. Hornykiewicz et al., “Preferential loss of serotonin markers in caudate versus putamen in Parkinson's disease,” Brain, vol. 131, no. 1, pp. 120–131, 2008.
[114]
M. E. Castro, J. Pascual, T. Romón, J. Berciano, J. Figols, and A. Pazos, “5-HT(1B) receptor binding in degenerative movement disorders,” Brain Research, vol. 790, no. 1-2, pp. 323–328, 1998.
[115]
R. Quirion and J. Richard, “Differential effects of selective lesions of cholinergic and dopaminergic neurons on serotonin-type 1 receptors in rat brain,” Synapse, vol. 1, no. 1, pp. 124–130, 1987.
[116]
K. Ikeguchi and A. Kuroda, “Mianserin treatment of patients with psychosis induced by antiparkinsonian drugs,” European Archives of Psychiatry and Clinical Neuroscience, vol. 244, no. 6, pp. 320–324, 1995.
[117]
F. Durif, M. Vidailhet, F. Assal, C. Roche, A. M. Bonnet, and Y. Agid, “Low-dose clozapine improves dyskinesias in Parkinson's disease,” Neurology, vol. 48, no. 3, pp. 658–662, 1997.
[118]
G. Di Giovanni, V. Di Matteo, M. Pierucci, A. Benigno, and E. Esposito, “Serotonin involvement in the basal ganglia pathophysiology: could the 5-HT2c receptor be a new target for therapeutic strategies?” Current Medicinal Chemistry, vol. 13, no. 25, pp. 3069–3081, 2006.
[119]
P. De Deurwaerdère, L. Mignon, and M. F. Chesselet, “Physiological and pathophysiological aspects of 5-HT2C receptors in basal ganglia,” in The Pathophysiology of Central 5-HT2C Receptors, G. Di Giovanni and K. Neve, Eds., The receptors series, Humana Press, Springer, New York, NY, USA, 2010.
[120]
S. H. Fox, B. Moser, and J. M. Brotchie, “Behavioral effects of 5-HT(2C) receptor antagonism in the substantia nigra zona reticulata of the 6-hydroxydopamine-lesioned rat model of Parkinson's disease,” Experimental Neurology, vol. 151, no. 1, pp. 35–49, 1998.
[121]
S. H. Fox and J. M. Brotchie, “5-HT(2C) receptor antagonists enhance the behavioural response to dopamine D1 receptor agonists in the 6-hydroxydopamine-lesioned rat,” European Journal of Pharmacology, vol. 398, no. 1, pp. 59–64, 2000.
[122]
P. De Deurwaerdère and M. F. Chesselet, “Nigrostriatal lesions alter oral dyskinesia and c-Fos expression induced by the serotonin agonist 1-(m-chlorophenyl)piperazine in adult rats,” Journal of Neuroscience, vol. 20, no. 13, pp. 5170–5178, 2000.
[123]
M. Politis, K. Wu, C. Loane et al., “Staging of serotonergic dysfunction in Parkinson's Disease: an in vivo 11C-DASB PET study,” Neurobiology of Disease, vol. 40, no. 1, pp. 216–221, 2010.
[124]
A. Mu？oz, Q. Li, F. Gardoni et al., “Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of L-DOPA-induced dyskinesia,” Brain, vol. 131, no. 12, pp. 3380–3394, 2008.
[125]
G. M. Goodwin, R. J. De Souza, A. J. Wood, and A. R. Green, “The enhancement by lithium of the 5-HT(1A) mediated serotonin syndrome produced by 8-OH-DPAT in the rat: evidence for a post-synaptic mechanism,” Psychopharmacology, vol. 90, no. 4, pp. 488–493, 1986.
[126]
J. Yamada, Y. Sugimoto, and K. Horisaka, “The behavioural effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in mice,” European Journal of Pharmacology, vol. 154, no. 3, pp. 299–304, 1988.
[127]
W. L. Kuan, J. W. Zhao, and R. A. Barker, “The role of anxiety in the development of levodopa-induced dyskinesias in an animal model of Parkinson's disease, and the effect of chronic treatment with the selective serotonin reuptake inhibitor citalopram,” Psychopharmacology, vol. 197, no. 2, pp. 279–293, 2008.
[128]
L. F. Schettino, S. V. Adamovich, W. Hening, E. Tunik, J. Sage, and H. Poizner, “Hand preshaping in Parkinson's disease: effects of visual feedback and medication state,” Experimental Brain Research, vol. 168, no. 1-2, pp. 186–202, 2006.
[129]
A. Dagher and A. Nagano-Saito, “Functional and anatomical magnetic resonance imaging in Parkinson's disease,” Molecular Imaging and Biology, vol. 9, no. 4, pp. 234–242, 2007.
[130]
G. S. Robertson and H. A. Robertson, “Evidence that L-dopa-induced rotational behavior is dependent on both striatal and nigral mechanisms,” Journal of Neuroscience, vol. 9, no. 9, pp. 3326–3331, 1989.
[131]
A. Antonini, J. Schwarz, W. H. Oertel, O. Pogarell, and K. L. Leenders, “Long-term changes of striatal dopamine D2 receptors in patients with Parkinson's disease: a study with positron emission tomography and [11C]raclopride,” Movement Disorders, vol. 12, no. 1, pp. 33–38, 1997.
[132]
R. Kuriakose and A. J. Stoessl, “Imaging the nigrostriatal system to monitor disease progression and treatment-induced complications,” Progress in Brain Research, vol. 184, pp. 177–192, 2010.
[133]
E. V. Encarnacion and R. A. Hauser, “Levodopa-induced dyskinesias in Parkinson's disease: etiology, impact on quality of life, and treatments,” European Neurology, vol. 60, no. 2, pp. 57–66, 2008.
[134]
J. J. Soghomonian, “L-DOPA-induced dyskinesia in adult rats with a unilateral 6-OHDA lesion of dopamine neurons is paralleled by increased c-fos gene expression in the subthalamic nucleus,” European Journal of Neuroscience, vol. 23, no. 9, pp. 2395–2403, 2006.
[135]
P. Svenningsson, J. Arts, L. Gunne, and P. E. Andren, “Acute and repeated treatment with L-DOPA increase c-jun expression in the 6-hydroxydopamine-lesioned forebrain of rats and common marmosets,” Brain Research, vol. 955, no. 1-2, pp. 8–15, 2002.
[136]
Y. Xu, S. Sun, and X. Cao, “Effect of levodopa chronic administration on behavioral changes and fos expression in basal ganglia in rat model of PD,” Journal of Huazhong University of Science and Technology. Medical sciences, vol. 23, no. 3, pp. 258–262, 2003.
[137]
A. Berthet and E. Bezard, “Dopamine receptors and L-dopa-induced dyskinesia,” Parkinsonism and Related Disorders, vol. 15, supplement 4, pp. S8–S12, 2009.
[138]
P. Calabresi, P. Giacomini, D. Centonze, and G. Bernardi, “Levodopa-induced dyskinesia: a pathological form of striatal synaptic plasticity?” Annals of Neurology, vol. 47, no. 4, supplement 1, pp. S60–S69, 2000.
[139]
C. Guigoni, Q. Li, I. Aubert et al., “Involvement of sensorimotor, limbic, and associative basal ganglia domains in L-3,4-dihydroxyphenylalanine-induced dyskinesia,” Journal of Neuroscience, vol. 25, no. 8, pp. 2102–2107, 2005.
[140]
L. Gong, R. M. Kostrzewa, R. W. Fuller, and K. W. Perry, “Supersensitization of the oral response to SKF 38393 in neonatal 6-OHDA- lesioned rats is mediated through a serotonin system,” Journal of Pharmacology and Experimental Therapeutics, vol. 261, no. 3, pp. 1000–1007, 1992.
[141]
A. Beyeler, N. Kadiri, S. Navailles et al., “Stimulation of serotonin2C receptors elicits abnormal oral movements by acting on pathways other than the sensorimotor one in the rat basal ganglia,” Neuroscience, vol. 169, no. 1, pp. 158–170, 2010.
[142]
S. Kapur and G. Remington, “Serotonin-dopamine interaction and its relevance to schizophrenia,” American Journal of Psychiatry, vol. 153, no. 4, pp. 466–476, 1996.
[143]
J. F. Liégeois, J. Ichikawa, and H. Y. Meltzer, “5-HT2A receptor antagonism potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and inhibits that in the nucleus accumbens in a dose-dependent manner,” Brain Research, vol. 947, no. 2, pp. 157–165, 2002.
[144]
G. Meco, P. Stirpe, F. Edito et al., “Aripiprazole in l-dopa-induced dyskinesias: a one-year open-label pilot study,” Journal of Neural Transmission, vol. 116, no. 7, pp. 881–884, 2009.
[145]
M. Carlsson and A. Carlsson, “Interactions between glutamatergic and monoaminergic systems within the basal ganglia—implications for schizophrenia and Parkinson's disease,” Trends in Neurosciences, vol. 13, no. 7, pp. 272–276, 1990.
[146]
E. Wolf, K. Seppi, R. Katzenschlager et al., “Long-term antidyskinetic efficacy of amantadine in Parkinson's disease,” Movement Disorders, vol. 25, no. 10, pp. 1357–1363, 2010.
[147]
S. Navailles and P. De Deurwaerdère, “Presynaptic control of serotonin on striatal dopamine function,” Psychopharmacology, vol. 213, no. 2-3, pp. 213–242, 2010.
[148]
B. Gomez-Mancilla and P. J. Bedard, “Effect of nondopaminergic drugs on L-DOPA-induced dyskinesias in MPTP- treated monkeys,” Clinical Neuropharmacology, vol. 16, no. 5, pp. 418–427, 1993.
[149]
C. G. Goetz, P. Damier, C. Hicking et al., “Sarizotan as a treatment for dyskinesias in Parkinson's disease: a double-blind placebo-controlled trial,” Movement Disorders, vol. 22, no. 2, pp. 179–186, 2007.
[150]
K. L. Eskow, V. Gupta, S. Alam, J. Y. Park, and C. Bishop, “The partial 5-HT1A agonist buspirone reduces the expression and development of l-DOPA-induced dyskinesia in rats and improves l-DOPA efficacy,” Pharmacology Biochemistry and Behavior, vol. 87, no. 3, pp. 306–314, 2007.
[151]
K. Kannari, K. Kurahashi, M. Tomiyama et al., “Tandospirone citrate, a selective 5-HT1A agonist, alleviates L-DOPA-induced dyskinesia in patients with Parkinson's disease,” Brain and Nerve, vol. 54, no. 2, pp. 133–137, 2002.
[152]
M. M. Iravani, K. Tayarani-Binazir, W. B. Chu, M. J. Jackson, and P. Jenner, “In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates, the selective 5-hydroxytryptamine 1a agonist (R)-(+)-8-OHDPAT inhibits levodopa-induced dyskinesia but only with\ increased motor disability,” Journal of Pharmacology and Experimental Therapeutics, vol. 319, no. 3, pp. 1225–1234, 2006.
[153]
M. Tomiyama, T. Kimura, T. Maeda, K. Kannari, M. Matsunaga, and M. Baba, “A serotonin 5-HT1A receptor agonist prevents behavioral sensitization to L-DOPA in a rodent model of Parkinson's disease,” Neuroscience Research, vol. 52, no. 2, pp. 185–194, 2005.
