Key Points
-
Levodopa-induced dyskinesia (LID) is a common complication after dopamine-replacement therapy in Parkinson's disease. The neural mechanisms underlying LID are far from clear, although significant advances have been made in recent years.
-
It is commonly assumed that levodopa induces dyskinesia by excessive inhibition of neurons of the projection from the putamen to the external segment of the globus pallidus (GPe), and subsequent disinhibition of the GPe. This dishinibition leads, in turn, to overinhibition of the subthalamic nucleus (STN) and to subsequent hypoactivity in output neurons of the basal ganglia. The net effect of these imbalances would be reduced inhibition of thalamocortical neurons and overactivation of cortical motor areas.
-
Marked abnormalities of neuronal function seem to accompany LID. They include changes in blood flow in the basal ganglia and in cortical motor areas, metabolic changes in the motor thalamus and internal segment of the globus pallidus (GPi), and alterations in the frequency and pattern of firing of GPi neurons.
-
Denervation supersensitivity of dopamine receptors has been widely suggested as the most plausible mechanism to underlie LID. This supersensitivity might be the result of changes in receptor number and cellular distribution, or changes in the signalling pathways downstream of receptor activation. As enhanced D1 dopamine receptor function might accompany the generation of dyskinesia, it is possible that the mechanisms underlying LID involve the direct pathway. This finding is surprising because, as described above, the neural mechanisms of dyskinesia are generally thought to involve the indirect rather than the direct pathway. Whereas the indirect pathway influences the output structures indirectly through a series of connections that involves the GPe and STN, the direct pathway comprises striatal neurons that project directly to the GPi and the substantia nigra.
-
Other neurotransmitters could also participate in the pathogenesis and treatment of LID. They include glutamate, enkephalins and opioid peptides. In fact, significant attention has been focused on the possibility that, in addition to the conventional dopamine-related therapeutic approaches, new pharmacological agents that are effective against these other neurotransmitter systems might be effective in treating LID.
Abstract
Involuntary movements — or dyskinesias — are a debilitating complication of levodopa therapy for Parkinson's disease that is experienced by most patients. Despite the importance of this problem, little was known about the cause of dyskinesia until recently; however, this situation has changed significantly in the past few years. Our increased understanding of levodopa-induced dyskinesia is not only valuable for improving patient care, but also in providing us with new insights into the functional organization of the basal ganglia and motor systems.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Parkinson, J. An Essay on the Shaking Palsy (Sherwood, Neely & Jones, London, 1817).
Ehringer, H. & Hornykiewicz, O. Verteilung von Noradrenalin und Dopamin (3-Hydroxytyramin) im Gehirn des Menschen und ihr Verhalten bei Erkrankungen des extrapyramidalen Systems. Klin. Wschr. 38, 1236–1239 (1960).
Carlsson, A., Lindquist, M. & Magnusson, T. 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 180, 1200 (1957).First experimental study showing reversal of reserpine-induced akinesia by levodopa administration.
Birkmayer, W. & Hornykiewicz, O. Der L-Dioxyphenylalanin effekt bei der Parkinson-Akinese. Wien. klin. Wschr. 73, 787–788 (1961).Early study showing the marked benefit of using levodopa to treat patients with Parkinson's disease.
Fahn, S. 'On–off' phenomenon with levodopa therapy in parkinsonism. Clinical and pharmacologic correlations and the effect of intramuscular pyridoxine. Neurology 24, 431–441 (1974).
Duvoisin, R. C. Variations in the 'on–off' phenomenon. Adv. Neurol. 5, 339–340 (1974).
Marsden, C. D. & Parkes, J. D. 'On–off' effects in patients with Parkinson's disease on chronic levodopa therapy. Lancet 1, 292–296 (1976).
Marsden, C. D., Parkes, J. D. & Quinn, N. in Movement Disorders (eds Marsden, C. D. & Fahn, S.) 96–122 (Butterworth, London, 1982).
Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson's disease in DATATOP patients requiring levodopa. Ann. Neurol. 39, 37–45 (1996).
Quinn, N. Drug treatment of Parkinson's disease. BMJ 310, 575–579 (1995).
Rascol, O. et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. N. Engl. J. Med. 342, 1484–1491 (2000).
Alexander, G. E., DeLong, M. R. & Strick, P. L. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu. Rev. Neurosci. 9, 357–381 (1986).
Alexander, G. E. & Crutcher, M. D. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci. 13, 266–271 (1990).
DeLong, M. R. Primate models of movement disorders of basal ganglia origin. Trends Neurosci. 13, 281–285 (1990).
Penney, J. B. & Young, A. B. Speculations on the functional anatomy of basal ganglia disorders. Annu. Rev. Neurosci. 6, 73–94 (1983).
Bezard, E., Crossman, A. R., Gross, C. E. & Brotchie, J. M. Structures outside the basal ganglia may compensate for dopamine loss in the pre-symptomatic stages of Parkinson's disease. FASEB J. 15, 1092–1094 (2001).
Rascol, O. et al. Supplementary and primary sensory motor area activity in Parkinson's disease: regional cerebral blood flow changes during finger movements and effects of apomorphine. Arch. Neurol. 49, 144–148 (1992).
Crossman, A. R. Primate models of dyskinesia: the experimental approach to the study of basal ganglia related involuntary movement disorders. Neuroscience 21, 1–40 (1987).
Crossman, A. R. A hypothesis on the pathophysiological mechanisms that underlie levodopa- or dopamine-agonist-induced dyskinesia in Parkinson's disease: implications for future strategies in treatment. Mov. Disord. 5, 100–108 (1990).
Cotzias, G. C., Papavasiliou, P. S. & Gellene, R. Modification of Parkinsonism — chronic treatment with L-dopa. N. Engl. J. Med. 280, 337–345 (1969).One of the first reports of LID. The authors also noted that dyskinesias do not occur during the first weeks of treatment, but later, during follow-up.
Yahr, M. D., Duvoisin, R. C., Hoehn, M. M., Schear, M. J. & Barrett, R. E. L-Dopa: its clinical effects in parkinsonism. Trans. Am. Neurol. Assoc. 93, 56–63 (1968).
Melamed, E. Early-morning dystonia. A late side effect of long-term levodopa therapy in Parkinson's disease. Arch. Neurol. 36, 308–310 (1979).
Muenter, M. D., Sharpless, N. S., Tyce, G. M. & Darley, F. L. Patterns of dystonia ('I-D-I' and 'D-I-D') in response to L-dopa therapy for Parkinson's disease. Mayo Clin. Proc. 52, 163–174 (1977).
Klawans, H. L., Goetz, C. & Bergen, D. Levodopa-induced myoclonus. Arch. Neurol. 32, 330–334 (1975).
Engber, T. M., Susel, Z., Juncos, J. L. & Chase, T. N. Continuous and intermittent levodopa differentially affect rotation induced by D-1 and D-2 dopamine agonists. Eur. J. Pharmacol. 168, 291–298 (1989).
Cenci, M. A., Lee, C. S. & Bjorklund, A. 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 (1998).
Henry, B., Crossman, A. R. & Brotchie, J. M. Effect of repeated L-DOPA, bromocriptine, or lisuride administration on preproenkephalin-A and preproenkephalin-B mRNA levels in the striatum of the 6-hydroxydopamine-lesioned rat. Exp. Neurol. 155, 204–220 (1999).
Langston, J. W., Ballard, P. A., Tetrud, J. W. & Irwin, I. Chronic parkinsonism in human due to a product of meperidine analog synthesis. Science 219, 979–980 (1983).
Langston, J. W. & Ballard, P. Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): implications for treatment and the pathogenesis of Parkinson's disease. Can. J. Neurol. Sci. 11, 160–165 (1984).
Brotchie, J. M. & Fox, S. H. Quantitative assessment of dyskinesias in subhuman primates. Mov. Disord. 14, 40–47 (1999).
Boraud, T., Bezard, E., Bioulac, B. & Gross, C. in The Basal Ganglia VI (ed. Graybiel, A.) (Kluwer Academic, Norwell, in the press).
Boraud, T., Bezard, E., Guehl, D., Bioulac, B. & Gross, C. Effects of L-DOPA on neuronal activity of the globus pallidus externalis (GPe) and globus pallidus internalis (GPi) in the MPTP-treated monkey. Brain Res. 787, 157–160 (1998).
Mitchell, I. J., Boyce, S., Sambrook, M. A. & Crossman, A. R. A 2-deoxyglucose study of the effects of dopamine agonists on the parkinsonian primate brain. Implications for the neural mechanisms that mediate dopamine agonist-induced dyskinesia. Brain 115, 809–824 (1992).Systematic study of activity changes within the basal ganglia in dyskinetic monkeys that showed either chorea or dystonia. An example of what is required in terms of defining experimental groups according to the clinical phenomenology.
Vila, M. et al. Consequences of nigrostriatal denervation on the functioning of the basal ganglia in human and nonhuman primates: an in situ hybridization study of cytochrome oxidase subunit I mRNA. J. Neurosci. 17, 765–773 (1997).
Papa, S. M., Desimone, R., Fiorani, M. & Oldfield, E. H. Internal globus pallidus discharge is nearly suppressed during levodopa-induced dyskinesias. Ann. Neurol. 46, 732–738 (1999).
Lozano, A. M., Lang, A. E., Levy, R., Hutchison, W. & Dostrovsky, J. Neuronal recordings in Parkinson's disease patients with dyskinesias induced by apomorphine. Ann. Neurol. 47, S141–146 (2000).
Filion, M., Tremblay, L. & Bedard, P. J. Effects of dopamine agonists on the spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res. 547, 152–161 (1991).
Mitchell, I. J. et al. Neural mechanisms underlying parkinsonian symptoms based upon regional uptake of 2-deoxyglucose in monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neuroscience 32, 213–226 (1989).
Filion, M. Effects of interruption of the nigrostriatal pathway and of dopaminergic agents on the spontaneous activity of globus pallidus neurons in the awake monkey. Brain Res. 178, 425–441 (1979).Early electrophysiological study in a primate model of Parkinson's disease, showing that apomorphine fully inhibits GPi neuronal discharge.
Boraud, T., Bezard, E., Bioulac, B. & Gross, C. Dopamine agonist-induced dyskinesias are correlated to both firing pattern and frequency alteration of pallidal neurons in the MPTP-treated monkey. Brain 124, 546–557 (2001).The most complete study on both firing frequency and firing pattern modifications in relation to the time course and the onset of clinical improvement and dyskinesias.
Hutchinson, W. D., Levy, R., Dostrovsky, J. O., Lozano, A. M. & Lang, A. E. Effects of apomorphine on globus pallidus neurons in parkinsonian patients. Ann. Neurol. 42, 767–775 (1997).
Stefani, A. et al. Effects of increasing doses of apomorphine during stereotaxic neurosurgery in Parkinson's disease: clinical score and internal globus pallidus activity. J. Neural Transm. 104, 895–904 (1997).
Brooks, D. J., Piccini, P., Turjanski, N. & Samuel, M. Neuroimaging of dyskinesia. Ann. Neurol. 47, S154–159 (2000). | PubMed |
Rascol, O. et al. Cortical motor overactivation in parkinsonian patients with L-dopa-induced peak-dose dyskinesia. Brain 121, 527–533 (1998).
Lozano, A. M. & Lang, A. E. Pallidotomy for Parkinson's disease. Neurosurg. Clin. N. Am. 9, 325–336 (1998).
Ng, K. Y., Chase, T. N., Colburn, R. W. & Kopin, I. J. L-Dopa-induced release of cerebral monoamines. Science 170, 76–77 (1970).
Melamed, E., Hefti, F., Liebman, J., Schlosberg, A. J. & Wurtman, R. J. Serotonergic neurones are not involved in action of L-dopa in Parkinson's disease. Nature 283, 772–774 (1980).Initial finding of the lack of involvement of serotonin terminals in levodopa transformation.
Melamed, E., Hefti, F., Pettibone, D. J., Liebman, J. & Wurtman, R. J. Aromatic L-amino acid decarboxylase in rat corpus striatum: implications for action of L-dopa in parkinsonism. Neurology 31, 651–655 (1981).Demonstration that non-aminergic striatal neurons convert exogenous levodopa to dopamine in parkinsonism.
Lopez, A., Munoz, A., Guerra, M. J. & Labandeira-Garcia, J. L. Mechanisms of the effects of exogenous levodopa on the dopamine-denervated striatum. Neuroscience 103, 639–651 (2001).
Nutt, J. G., Obeso, J. A. & Stocchi, F. Continuous dopamine-receptor stimulation in advanced Parkinson's disease. Trends Neurosci. 23, S109–115 (2000).Most recent review of continuous versus pulsatile delivery of dopamine agents in Parkinson's disease.
Olanow, W., Schapira, A. H. & Rascol, O. Continuous dopamine-receptor stimulation in early Parkinson's disease. Trends Neurosci. 23, S117–126 (2000).
Colzi, A., Turner, K. & Lees, A. J. Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa induced interdose dyskinesias in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 64, 573–576 (1998).
Quinn, N., Parkes, J. D. & Marsden, C. D. Control of on/off phenomenon by continuous intravenous infusion of levodopa. Neurology 34, 1131–1136 (1984).
Marion, M. H., Stocchi, F., Quinn, N. P., Jenner, P. & Marsden, C. D. Repeated levodopa infusions in fluctuating Parkinson's disease: clinical and pharmacokinetic data. Clin. Neuropharmacol. 9, 165–181 (1986).
Olanow, C. W. & Obeso, J. A. Preventing levodopa-induced dyskinesias. Ann. Neurol. 47, S167–178 (2000).
Feuerstein, C. et al. Plasma O-methyldopa in levodopa-induced dyskinesias. A bioclinical investigation. Acta Neurol. Scand. 56, 508–524 (1977).
Montgomery, E. B. Jr Pharmacokinetics and pharmacodynamics of levodopa. Neurology 42, 17–22 (1992).
Breier, A. et al. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc. Natl Acad. Sci. USA 94, 2569–2574 (1997).
Tedroff, J. et al. L-Dopa modulates striatal dopaminergic function in vivo: evidence from PET investigations in nonhuman primates. Synapse 25, 56–61 (1997).
Tedroff, J. et al. Levodopa-induced changes in synaptic dopamine in patients with Parkinson's disease as measured by [11C]raclopride displacement and PET. Neurology 46, 1430–1436 (1996).
De la Fuente-Fernandez, R. et al. Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson's disease: PET evidence of increased dopamine turnover. Ann. Neurol. 49, 298–303 (2001).
Lee, T., Seeman, P., Rajput, A., Farley, I. J. & Hornykiewicz, O. Receptor basis for dopaminergic supersensitivity in Parkinson's disease. Nature 273, 150–151 (1978).
Creese, I., Burt, D. R. & Snyder, S. H. Dopamine receptor binding enhancement accompanies lesion-induced behavioral supersensitivity. Science 197, 596–598 (1977).
Graham, W. C., Sambrook, M. A. & Crossman, A. R. Differential effect of chronic dopaminergic treatment on dopamine D1 and D2 receptors in the monkey brain in MPTP-induced parkinsonism. Brain Res. 602, 290–303 (1993).
Gerfen, C. R. et al. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250, 1429–1432 (1990).
Shinotoh, H., Hirayama, K. & Tateno, Y. Dopamine D1 and D2 receptors in Parkinson's disease and striatonigral degeneration determined by PET. Adv. Neurol. 60, 488–493 (1993).
Brooks, D. J. et al. Striatal D2 receptor status in patients with Parkinson's disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and positron emission tomography. Ann. Neurol. 31, 184–192 (1992).
Shinotoh, H. et al. Dopamine D1 receptors in Parkinson's disease and striatonigral degeneration: a positron emission tomography study. J. Neurol. Neurosurg. Psychiatry 56, 467–472 (1993).
Levey, A. I. et al. Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies. Proc. Natl Acad. Sci. USA 90, 8861–8885 (1993).
Dumartin, B., Caillé, I., Gonon, F. & Bloch, B. Internalization of D1 dopamine receptor in striatal neurons in vivo as evidence of activation by dopamine agonists. J. Neurosci. 18, 1650–1651 (1998).
Muriel, M. P. et al. Levodopa induces a cytoplasmic localization of D1 dopamine receptors in striatal neurons in Parkinson's disease. Ann. Neurol. 46, 103–111 (1999).First demonstration of D1 dopamine receptor internalization in Parkinson's disease.
Walaas, S. I., Aswaad, S. W. & Greengard, P. A dopamine- and cyclic AMP-regulated phosphoprotein enriched in dopamine-innervated brain regions. Nature 301, 69–71 (1983).
Gerfen, C. R. Molecular effects of dopamine on striatal-projection pathways. Trends Neurosci. 23, S64–70 (2000). | PubMed |
Berke, J. D., Paletzki, R. F., Aronson, G. J., Hyman, S. E. & Gerfen, C. R. A complex program of striatal gene expression induced by dopaminergic stimulation. J. Neurosci. 18, 5301–5310 (1998).
Gerfen, C. R., Keefe, K. A. & Gauda, E. B. D1 and D2 dopamine receptor function in the striatum: coactivation of D1- and D2-dopamine receptors on separate populations of neurons results in potentiated immediate early gene responses in D1-containing neurons. J. Neurosci. 15, 8167–8176 (1995).Induction of immediate-early genes in striatal neurons would reflect the switch in receptor-mediated signal transduction mechanisms to produce a supersensitive form of D1-mediated neuronal plasticity.
Steiner, H. & Gerfen, C. R. Dynorphin regulates D1 dopamine receptor-mediated responses in the striatum: relative contributions of pre- and postsynaptic mechanisms in dorsal and ventral striatum demonstrated by altered immediate-early gene expression. J. Comp. Neurol. 376, 530–541 (1996).
Gomez-Mancilla, B. & Bedard, P. J. Effect of D1 and D2 agonists and antagonists on dyskinesia produced by L-DOPA in MPTP-treated monkeys. J. Pharmacol. Exp. Ther. 259, 409–413 (1991).
Pearce, R. K., Banerji, T., Jenner, P. & Marsden, C. D. De novo administration of ropinirole and bromocriptine induces less dyskinesia than L-dopa in the MPTP-treated marmoset. Mov. Disord. 13, 234–241 (1998).
Rascol, O. Medical treatment of levodopa-induced dyskinesias. Ann. Neurol. 47, S179–188 (2000).
Aizman, O. et al. Anatomical and physiological evidence for D-1 and D-2 dopamine receptor colocalization in neostriatal neurons. Nature Neurosci. 3, 226–230 (2000).
Levesque, D. et al. Identification, characterization, and localization of the dopamine D3 receptor in rat brain using 7-[3H]hydroxy-N,N-di-n-propyl-2-aminotetralin. Proc. Natl Acad. Sci. USA 89, 8155–8159 (1992).
Sokoloff, P., Giros, B., Martres, M.-P., Bouthenet, M.-L. & Schwartz, J.-C. Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347, 146–151 (1990).
Levesque, D. et al. A paradoxical regulation of the dopamine D3 receptor expression suggests the involvement of an anterograde factor from dopamine neurons. Proc. Natl Acad. Sci. USA 92, 1719–1723 (1995).
Bordet, R. et al. Induction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa. Proc. Natl Acad. Sci. USA 94, 3363–3367 (1997).Proof-of-principle study showing the crucial role of the ectopic expression of the dopamine D3 receptor in levodopa sensitization.
Pilla, M. et al. Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist. Nature 400, 371–375 (1999).
Bordet, R., Ridray, S., Schwartz, J. C. & Sokoloff, P. Involvement of the direct striatonigral pathway in levodopa-induced sensitization in 6-OHDA-lesioned rats. Eur. J. Neurosci. 12, 2117–2123 (2000).
Gross, C. E., Boraud, T., Guehl, D., Bioulac, B. & Bezard, E. From experimentation to the surgical treatment of Parkinson's disease: prelude or suite in basal ganglia research? Prog. Neurobiol. 59, 509–532 (1999).
Parent, A. & Hazrati, L.-N. Functional anatomy of the basal ganglia. I. The cortico–basal ganglia–thalamo–cortical loop. Brain Res. Rev. 20, 91–127 (1995).
Kotter, R. Postsynaptic integration of glutamatergic and dopaminergic signals in the striatum. Prog. Neurobiol. 44, 163–196 (1994).
Calabresi, P., Pisani, A., Mercuri, N. B. & Bernardi, G. The corticostriatal projection: from synaptic plasticity to dysfunctions of the basal ganglia. Trends Neurosci. 19, 19–24 (1996).
Calabresi, P., Pisani, A., Centonze, D. & Bernardi, G. Synaptic plasticity and physiological interactions between dopamine and glutamate in the striatum. Neurosci. Biobehav. Rev. 21, 519–523 (1997).
Calabresi, P. et al. Synaptic transmission in the striatum: from plasticity to neurodegeneration. Prog. Neurobiol. 61, 231–265 (2000).
Tang, K. C., Low, M. J., Grandy, D. K. & Lovinger, D. M. Dopamine-dependent synaptic plasticity in striatum during in vivo development. Proc. Natl Acad. Sci. USA 98, 1255–1260 (2001).
Dunah, A. W. et al. Alterations in subunit expression, composition, and phosphorylation of striatal N-methyl-d-aspartate glutamate receptors in a rat 6-hydroxydopamine model of Parkinson's disease. Mol. Pharmacol. 57, 342–352 (2000).
Ganguly, A. & Keefe, K. A. Unilateral dopamine depletion increases expression of the 2A subunit of the N-methyl-d-aspartate receptor in enkephalin-positive and enkephalin-negative neurons. Neuroscience 103, 405–412 (2001).
Ingham, C. A., Hood, S. H., Maldegem, V. B., Weenink, A. & Arbuthnott, G. W. Morphological changes in the rat neostriatum after unilateral 6-hydroxydopamine injections into the nigrostriatal pathway. Exp. Brain Res. 93, 17–27 (1993).
Menegoz, M., Lau, L. F., Herve, D., Huganir, R. L. & Girault, J. A. Tyrosine phosphorylation of NMDA receptor in rat striatum: effects of 6-OHDA lesions. Neuroreport 7, 125–128 (1995).
Del Fiacco, M., Paxinos, G. & Cuello, A. C. Neostriatal enkephalin-immunoreactive neurons project to the globus pallidus. Brain Res. 231, 1–17 (1982).
Maneuf, Y. P., Mitchell, I. J., Crossman, A. R. & Brotchie, J. M. On the role of enkephalin cotransmission in the GABAergic striatal efferents to the globus pallidus. Exp. Neurol. 125, 65–71 (1994).
Dewar, D., Jenner, P. & Marsden, C. D. Effects of opioid agonist drugs on the in vitro release of [3H]-GABA, [3H]-dopamine and [3H]-5HT from slices of rat globus pallidus. Biochem. Pharmacol. 36, 1738–1741 (1987).
Henry, B. & Brotchie, J. M. Potential of opioid antagonists in the treatment of levodopa-induced dyskinesias in Parkinson's disease. Drugs Aging 9, 149–158 (1996).
Herrero, M. T. et al. Effects of L-dopa on preproenkephalin and preprotachykinin gene expression in the MPTP-treated monkey striatum. Neuroscience 68, 1189–1198 (1995).
Morissette, M., Grondin, R., Goulet, M., Bedard, P. J. & Di Paolo, T. Differential regulation of striatal preproenkephalin and preprotachykinin mRNA levels in MPTP-lesioned monkeys chronically treated with dopamine D-1 or D-2 receptor agonists. J. Neurochem. 72, 682–692 (1999).
Zeng, B. Y., Pearce, R. K. B., MacKenzie, G. M. & Jenner, P. Alterations in preproenkephalin and adenosine-2a receptor mRNA, but not preprotachykinin mRNA correlate with occurrence of dyskinesia in normal monkeys chronically treated with L-DOPA. Eur. J. Neurosci. 12, 1096–1104 (2000).
Mehta, A., Bot, G., Reisine, T. & Chesselet, M. F. Endomorphin-1: induction of motor behavior and lack of receptor desensitization. J. Neurosci. 21, 4436–4442 (2001).
Gerfen, C. R., McGinty, J. F. & Young, W. S. Dopamine differentially regulates dynorphin, substance P, and enkephalin expression in striatal neurons: in situ hybridization histochemical analysis. J. Neurosci. 11, 1016–1031 (1991).
Engber, T. M., Susel, Z., Kuo, S., Gerfen, C. R. & Chase, T. N. Levodopa replacement therapy alters enzyme activities in striatum and neuropeptide content in striatal output regions of 6-hydroxydopamine lesioned rats. Brain Res. 552, 113–118 (1991).
Maneuf, Y. P., Mitchell, I. J., Crossman, A. R., Woodruff, G. N. & Brotchie, J. M. Functional implications of κ-opioid receptor-mediated modulation of glutamate transmission in the output regions of the basal ganglia in rodent and primate models of Parkinson's disease. Brain Res. 683, 102–108 (1995).
Hill, M. P. Modulation of glutamate release by κ-opioid receptor agonist in rodent and primate striatum. Eur. J. Pharmacol. 281, R1–2 (1995).
Stoessl, A. J., Polanski, E. & Frydryszak, H. The opiate antagonist naloxone suppresses a rodent model of tardive dyskinesia. Mov. Disord. 8, 445–452 (1993).
Piccini, P., Weeks, R. A. & Brooks, D. J. Alterations in opioid receptor binding in Parkinson's disease patients with levodopa-induced dyskinesias. Ann. Neurol. 42, 720–726 (1997).
Johansson, P. A., Andersson, M., Andersson, K. E. & Cenci, M. A. Alterations in cortical and basal ganglia levels of opioid receptor binding in a rat model of L-DOPA-induced dyskinesia. Neurobiol. Dis. 8, 220–239 (2001).
Brotchie, J. M. Adjuncts to dopamine replacement: a pragmatic approach to reducing the problem of dyskinesia in Parkinson's disease. Mov. Disord. 13, 871–876 (1998).
Rascol, O. et al. Induction by dopamine D-1 receptor agonist ABT-431 of dyskinesia similar to levodopa in patients with Parkinson disease. Arch. Neurol. 58, 249–254 (2001).
Sokoloff, P. From cloning to therapeutic: example of the D3 dopamine receptor. 5° Colloque de la Société des Neurosciences 5, 14 (2001).
Dziewczapolski, G. et al. Opposite roles of D1 and D5 dopamine receptors in locomotion revealed by selective antisense oligonucleotides. Neuroreport 9, 1–5 (1998).
Papa, S. M. & Chase, T. N. Levodopa-induced dyskinesias improved by a glutamate antagonist in parkinsonian monkeys. Ann. Neurol. 39, 574–578 (1996).
Blanchet, P. J., Konitsiotis, S. & Chase, T. N. Amantadine reduces levodopa-induced dyskinesias in parkinsonian monkeys. Mov. Disord. 13, 798–802 (1998).
Blanchet, P. J. et al. Differing effects of N-methyl-d-aspartate receptor subtype selective antagonists on dyskinesias in levodopa-treated 1-methyl-4-phenyl- tetrahydropyridine monkeys. J. Pharmacol. Exp. Ther. 290, 1034–1040 (1999).
Verhagen Metman, L. et al. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's disease. Neurology 50, 1323–1326 (1998).
Luginger, E., Wenning, G. K., Bosch, S. & Poewe, W. Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson's disease. Mov. Disord. 15, 873–878 (2000).
Konitsiotis, S., Blanchet, P. J., Verhagen, L., Lamers, E. & Chase, T. N. AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkeys. Neurology 54, 1589–1595 (2000).
Trabucchi, M., Bassi, S. & Frattola, L. Effect of naloxone on the 'on–off' syndrome in patients receiving long-term levodopa therapy. Arch. Neurol. 39, 120–121 (1982).
Sandyk, R. & Snider, S. R. Naloxone treatment of L-dopa-induced dyskinesias in Parkinson's disease. Am. J. Psychiatry 143, 118 (1986).
Manson, A. J., Katzenschlager, R., Hobart, J. & Lees, A. J. High dose naltrexone for dyskinesias induced by levodopa. J. Neurol. Neurosurg. Psychiatry 70, 554–556 (2001).
Nutt, J. G., Rosin, A. J., Eisler, T., Calne, D. B. & Chase, T. N. Effect of an opiate antagonist on movement disorders. Arch. Neurol. 35, 810–811 (1978).
Rascol, O. et al. Naltrexone, an opiate antagonist, fails to modify motor symptoms in patients with Parkinson's disease. Mov. Disord. 9, 437–440 (1994).
Schiffmann, S. N., Jacobs, O. & Vanderhaeghen, J. J. Striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons: an in situ hybridization histochemistry study. J. Neurochem. 57, 1062–1067 (1991).
Svenningsson, P. et al. Cellular distribution of adenosine A2A receptor mRNA in the primate striatum. J. Comp. Neurol. 399, 229–240 (1998).
Nash, J. E. & Brotchie, J. M. A common signaling pathway for striatal NMDA and adenosine A2a receptors: implications for the treatment of Parkinson's disease. J. Neurosci. 20, 7782–7789 (2000).
Kanda, T. et al. Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. Ann. Neurol. 43, 507–513 (1998).
Jenner, P. Pathophysiology and biochemistry of dyskinesia: clues for the development of non-dopaminergic treatments. J. Neurol. 247, II43–50 (2000).
Brotchie, J. M. et al. Cannabinoid receptors and L-DOPA-induced dyskinesia in Parkinson's disease. Soc. Neurosci. Abstr. 24 (1998).
Fox, S. H., Hill, M. P., Crossman, A. R. & Brotchie, J. M. On the role of endocannabinoids in L-DOPA-induced dyskinesia. Soc. Neurosci. Abstr. 25, 1462 (1999).
Bezard, E. et al. Effects of the α2-adrenoreceptor antagonist, idazoxan, on motor disabilities in MPTP-treated monkey. Prog. Neuropsychopharmacol. Biol. Psychiatry 23, 1237–1246 (1999).
Colpaert, F. C., Degryse, A. D. & VanCraenendonck, H. Effects of an α2 antagonist in a 20-year-old java monkey with MPTP-induced parkinsonian signs. Brain Res. Bull. 26, 627–631 (1991).
Henry, B., Fox, S. H., Peggs, D., Crossman, A. R. & Brotchie, J. M. The α2-adrenergic receptor antagonist idazoxan reduces dyskinesia and enhances anti-parkinsonian actions of L-dopa in the MPTP-lesioned primate model of Parkinson's disease. Mov. Disord. 14, 744–753 (1999).
Gomez-Mancilla, B. & Bedard, P. J. Effect of nondopaminergic drugs on L-DOPA-induced dyskinesias in MPTP-treated monkeys. Clin. Neuropharmacol. 16, 418–427 (1993).
Brefel-Courbon, C. et al. α2-Adrenoceptor antagonists: a new approach to Parkinson's disease? CNS Drugs 10, 189–207 (1998).
Fox, S. H. et al. The neural mechanisms underlying peak-dose dyskinesia induced by levodopa and apomorphine are distinct: evidence from the effects of the α2-adrenoceptor antagonist idazoxan. Mov. Disord. (in the press).
Acknowledgements
We thank S. Fox for helpful discussion and comments during the preparation of the manuscript. E.B. was supported by a grant from the Société de Secours des Amis des Sciences. J.M.B. is supported by the Medical Research Council (UK) and the Parkinson's Disease Society (UK). The University of Manchester, the CNRS and the IFR of Neuroscience funded this review. Our apologies to the many authors whose work could not be quoted because of space limitations.
Author information
Authors and Affiliations
Supplementary information
41583_2001_BF35086062_MOESM1_ESM.htm
Links to patents referred to in Table 1 | Patent applications related to the treatment of levodopa-induced dyskinesia (HTM 2 kb)
Related links
Related links
DATABASE LINKS
Glossary
- BRADYKINESIA
-
Slowing of and difficulty in initiating movement that is characteristic of Parkinson's disease.
- ON–OFF FLUCTUATIONS
-
A sudden loss of levodopa-induced benefit ('on' state) and onset of the parkinsonian state ('off' state). The term 'on–off' depicts well the speed of this change in therapeutic benefit, which has been likened to switching a light on and off.
- WEARING-OFF PHENOMENON
-
A decrease in the duration of levodopa action, also known as the 'end-of-dose' deterioration. It is characterized by the gradual reappearance of the 'off' state, and shortening of the 'on' state.
- MEDIUM SPINY NEURONS
-
The main cell population of the ventral and dorsal striatum; these GABA-containing projection neurons form the two main outputs of these structures, called the direct and indirect pathways.
- BALLISM
-
Large-amplitude flinging, flailing movements, often associated with damage to the subthalamic nucleus.
- CHOREOATHETOSIS
-
A movement disorder that is characterized by constant writhing and jerking motions.
- MYOCLONUS
-
Brief, involuntary twitching of a muscle or a group of muscles. Familiar examples of normal myoclonus include hiccups and jerks experienced when drifting off to sleep.
- AKATHISIA
-
Motor restlessness associated with increased nervousness, jittery feeling and insomnia. It is often seen as a side effect of long-term antipsychotic treatment.
- 6-HYDROXYDOPAMINE MODEL
-
Unilateral administration of 6-OHDA to the substantia nigra of rodents leads to degeneration of the nigrostriatal dopamine pathway. The extent of dopamine depletion can then be assessed by examining circling behaviour in response to amphetamine and apomorphine.
- SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY
-
A method in which images are generated by using radionuclides that emit single photons of a given energy. Images are captured at multiple positions by rotating the sensor around the subject; the three-dimensional distribution of radionuclides is then used to reconstruct the images. SPECT can be used to observe biochemical and physiological processes, as well as the size and volume of structures. Unlike positron emission tomography, SPECT requires the physical alignment of the photons for their detection, resulting in the loss of many available photons and the degradation of the image.
- DIPRENORPHINE
-
A marker of μ-, κ- and δ-opioid receptors that is sensitive to the levels of endogenous opioids.
Rights and permissions
About this article
Cite this article
Bezard, E., Brotchie, J. & Gross, C. Pathophysiology of levodopa-induced dyskinesia: Potential for new therapies. Nat Rev Neurosci 2, 577–588 (2001). https://doi.org/10.1038/35086062
Issue Date:
DOI: https://doi.org/10.1038/35086062
This article is cited by
-
Translational molecular imaging and drug development in Parkinson’s disease
Molecular Neurodegeneration (2023)
-
Neuromodulation in Parkinson’s disease targeting opioid and cannabinoid receptors, understanding the role of NLRP3 pathway: a novel therapeutic approach
Inflammopharmacology (2023)
-
The Dynamics of Dopamine D2 Receptor-Expressing Striatal Neurons and the Downstream Circuit Underlying L-Dopa-Induced Dyskinesia in Rats
Neuroscience Bulletin (2023)
-
Why do ‘OFF’ periods still occur during continuous drug delivery in Parkinson’s disease?
Translational Neurodegeneration (2022)
-
Contracted thalamic shape is associated with early development of levodopa-induced dyskinesia in Parkinson’s disease
Scientific Reports (2022)