- Email: [email protected]
Plastic effects of L-DOPA treatment in the basal ganglia and their relevance to the development of dyskinesia
Parkinsonism and Related Disorders 15S3 (2009) S59–S63
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Plastic effects of L-DOPA treatment in the basal ganglia and their relevance to the development of dyskinesia M. Angela Cenci*, K. Elisabet Ohlin, Daniella Rylander Basal Ganglia Pathophysiology Unit, Dept. Experimental Medical Science, Lund University, BMC F11, 221 84 Lund, Sweden
article info
summary
Keywords: Dopamine receptor D1 Extracellular signal-regulated kinases 1 and 2 ERK1/2 Angiogenesis 5-Hydroxytryptamine Serotonin transporter Dopamine transporter
The development of L-DOPA-induced dyskinesia (LID) is attributed to plastic responses triggered by dopamine (DA) receptor stimulation in the parkinsonian brain. This article reviews studies that have uncovered different levels of maladaptive plasticity in animal models of LID. Rats developing dyskinesia on chronic L-DOPA treatment show abnormal patterns of signaling pathway activation and synaptic plasticity in striatal neurons. In addition, these animals show a gene expression profile indicative of structural cellular plasticity, including pronounced upregulation of genes involved in extracellular matrix remodeling, neurite extension, synaptic vesicle trafficking, and endothelial and cellular proliferation. Structural changes of neurons and microvessels within the basal ganglia are currently being unraveled by detailed morphological analyses. The structural and functional adaptations induced by L-DOPA in the brain can be viewed as an attempt to meet increased metabolic demands and to boost cellular defense mechanisms. These homeostatic responses, however, also predispose to the appearance of dyskinesia and other complications during the course of the treatment. © 2009 Elsevier Ltd. All rights reserved.
1. Introduction L-DOPA remains the most efficacious drug to treat the signs and symptoms of Parkinson’s disease, but it causes dyskinesia (abnormal involuntary movements) in the majority of the patients. L-DOPA-induced dyskinesia (LID) has been reported to occur in about 10% of patients per year in the first seven years of treatment [1], but the reported incidence of LID varies greatly between studies and patient groups [2]. Some people exhibit severe dyskinesias very rapidly, whereas others do not develop this complication despite many years of L-DOPA treatment. A generally accepted view holds that the susceptibility to LID is determined by the brain’s “plasticity potential” [3]. According to this view, LID is an aberrant form of neuroplasticity that is triggered by the combined effects of DA denervation and pharmacological DA replacement. The gradual development and persistence of LID suggest that a disorder of brain plasticity is implicated in its pathophysiology. Once developed, LID is very difficult to reduce or reverse, it is promptly elicited by L-DOPA even after long periods of treatment discontinuation, it is induced also by nondyskinesiogenic drugs (e.g. long-acting DA agonists), and it can be precipitated by stress (partly reviewed in [4]). The brain’s “plasticity potential” varies among individuals depending on age and genetics, and this has been proposed as an explanation to the varying susceptibility to dyskinesia in PD [3]. The group at highest * Corresponding author. E-mail address: [email protected] (M.A. Cenci). 1353-8020/$ – see front matter © 2009 Elsevier Ltd. All rights reserved.
risk of developing LID are young-onset PD patients (see [2] for review), who are supposedly endowed with the greatest potential for neuroplasticity within the parkinsonian patient population. The time to onset of LID in PD is influenced by a functional polymorphism in the gene coding for brain-derived neurotrophic factor (BDNF) [5], which is a prime mediator of neuroplasticity in health and disease (see below). Furthermore, using a paired associative stimulation protocol, abnormal plastic responses of the motor cortex have been evidenced in PD patients affected by LID [6]. Because corticostriatal synapses play a pivotal role in movement selection, many authors have attributed LID to an aberrant plasticity of corticostriatal synapses (reviewed in [4,7]). Studies in acute brain slices from L-DOPA-treated rats have indeed revealed an abnormal form of corticostriatal synaptic plasticity in dyskinetic animals, consisting in a failure to reverse long-term potentiation (LTP) upon low-frequency stimulation of the cortical afferent pathway [8]. Despite all these strong indicia, questions on the “why, where, and what” of abnormal plasticity mechanisms in LID are still wideopen. The studies of corticostriatal synaptic plasticity thus far performed are neither exhaustive nor conclusive (in particular, a causal link between the observed abnormality and the occurrence of dyskinesia has not yet been demonstrated). Moreover, in addition to corticostriatal synapses, many types of cells and circuits within the basal ganglia show plastic changes in animal models of LID. By reviewing different levels of plastic alterations in LID, this article will provide a brief survey on a presently scattered, but rapidly growing area of investigation.
S60
M.A. Cenci et al. / Parkinsonism and Related Disorders 15S3 (2009) S59–S63
2. Presynaptic plasticity Large intermittent fluctuations in brain levels of DA have been classically attributed a prime causal role in LID [9]. These fluctuations would be due to the loss of nigrostriatal DA neurons, which inevitably causes L-DOPA to be taken up and decarboxylated by brain cells that lack DA storage capacity (reviewed in [4]). Recent studies in animal models of LID and human PD patients suggest that the extent of nigrostriatal DA lesion is not the only determinant of the large DA fluctuations induced by L-DOPA (reviewed in [10]). The increase in extracellular DA levels post L-DOPA administration would be exaggerated by a reduced expression or dysfunction of the DA transporter (DAT) in residual nigrostriatal terminals [11,12], and by a high density of serotonergic axon fibers in the striatum [13]. Serotonin neurons express the enzymes required to convert L-DOPA to DA, and have the ability to store DA in synaptic vesicles, thus protecting it from cytosolic degradation. However, the uptake and conversion of exogenous L-DOPA by serotonin neurons result in non-regulated DA efflux and defective clearance of extracellular DA. In 6-OHDA-lesioned rats, treatment with the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) attenuates the L-DOPA-induced increase in striatal extracellular DA levels by 80% [14] and completely abolishes LID [15]. Agonists of serotonin 5-HT1A and 5-HT1B receptors, which reduce transmitter release from serotonergic neurons, exert pronounced antidyskinetic effects in animal models of LID [15]. The same agents blunt the peak of extracellular DA levels following peripheral L-DOPA administration [16].
which have been evidenced at both the light and the electron microscopic levels. Studies using the Golgi silver-impregnation technique in rats with 6-hydroxydopamine (6-OHDA) lesions have shown that the loss of DA input is rapidly followed by a decrease in the number of dendritic spines in striatal medium-sized spiny neurons, and that this structural modification is virtually permanent [23,24]. Interestingly, post-mortem studies in human PD patients have revealed changes in striatal neuron morphology similar to those observed in the rat model [25]. Because the patients had been treated with L-DOPA for many years, these results suggest that pharmacological dopaminergic therapies do not normalize the dendritic structure of striatal neurons. The treatment’s inability to restore structural features of the nigrostriatal microcircuitry is attracting growing attention as a potential mechanism in LID [7], but our current understanding of this mechanism is, at best, rudimentary. Only one published study thus far has addressed the impact of denervation-induced spine pruning on the development of LID [26]. In this study, a treatment that completely prevented the lesion-induced spine loss (i.e. continuous administration of the L-type calcium channel blocker, isradipine) achieved a partial attenuation of LID in 6-OHDA-lesioned rats [26]. There is an obvious need for further investigations addressing the role of striatal dendritic abnormalities in the pathophysiology of LID. In addition to the spine loss that follows DA denervation, it will be important to examine superimposed changes in dendritic morphology that occur upon treatment with L-DOPA. 4. Plasticity of the serotonin system and involvement of BDNF
3. Denervation-induced postsynaptic plasticity in the striatum Presynaptic abnormalities in the handling of exogenous L-DOPA cannot alone account for LID. Indeed, dyskinesias indistinguishable from those induced by L-DOPA are evoked by direct DA receptor agonists in both animal models [17] and PD patients [18]. Like LID, DA agonist-induced dyskinesias only occur when the nigrostriatal DA pathway is severely damaged. This argues for a critical role of postsynaptic mechanisms in the predisposition to LID caused by DA denervation. In this context, two types of postsynaptic changes are attributed a particularly important role. The first is a denervation-dependent supersensitivity of DA D1 receptors, which is emerging as a critical determinant of LID in both rodent and non-human primate models of PD (partially reviewed in [10]). This supersensitivity is not dependent on an increased number of D1 receptors, but reflects aberrant signaltransduction mechanisms. Both canonical (cyclic AMP-dependent) and non-canonical pathways show pronounced activation in DAdenervated striatal neurons upon treatment with either D1 receptor agonists or L-DOPA. In a seminal study, Gerfen and collaborators showed that treatment with D1 receptor agonists induces mitogenactivated protein kinases (MAPK) in striatonigral neurons in the DAdenervated but not the intact striatum [19]. The MAPK signaling system was originally discovered as a critical regulator of cell division and differentiation, and was later found to be recruited in mature neurons by different types of extracellular stimuli inducing long-term synaptic and behavioral adaptations [20]. It was later found that treatment with L-DOPA induces a pronounced striatal activation of p44 MAPK and p42 MAPK (most commonly referred to as extracellular signal-regulated kinases 1 and 2, ERK1/2) specifically in animals that develop dyskinesia [21,22]. The striatal levels of phosphorylated (active) ERK1/2 correlate positively both with the abnormal involuntary movement scores, and with the expression of nuclear signaling markers, such as the activation of histone kinases and the upregulation of DFosB-like transcription factors [22]. In addition to receptor supersensitivity, DA denervation causes changes in dendritic and synaptic morphology in striatal neurons,
Serotonin (5-hydroxytryptamine, 5-HT) is produced by neurons in the brainstem raphe nuclei, which send widespread projections to cortical and subcortical brain regions, modulating a wide array of functions, including sensorimotor control, cognition and mood. A closer look at this neuronal system is highly warranted given its crucial role in the generation of LID (at least in animal models), and its potential implication in the cognitive and psychiatric problems afflicting PD patients. Serotonin neurons show both a high vulnerability to neurodegeneration and a high capacity for neuroplasticity, and these processes are heavily influenced by brain derived neurotrophic factor (BDNF). This neurotrophin can enhance 5-HT biosynthesis, upregulate 5-HT uptake, potentiate depolarization-induced 5-HT release, and modify the firing pattern of 5-HT neurons (partly reviewed in [27]). In addition, BDNF has growth-promoting effects on 5-HT axons. Conversely, the serotonergic system promotes the expression of BDNF via 5-HT 4,5,6 receptors, whose downstream signaling cascades positively regulate BDNF gene transcription [27]. Because of their tight functional interactions, BDNF and 5-HT have been defined as a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders [28]. There is growing evidence of synergism between the 5-HT system and BDNF in the genetic susceptibility to affective disorders and in the response to antidepressant treatment (reviewed in [27,29]). Plastic responses involving the “5-HT-BDNF duo” have just started to be investigated in PD. A recent post-mortem study in PD patients found that several 5-HT markers (i.e. the 5-HT transporter protein, the 5-HT biosynthetic enzyme tryptophan hydroxylase, and the levels of 5-HT and its metabolite) were decreased by 30–66% in both cognitive and sensorimotor striatal domains, without any evident relationship with the occurrence or absence of LID [30]. The loss of 5-HT markers was thus interpreted as being a consequence of the neurodegenerative process in PD. Studies of the 5-HT system in animal models of PD have, however, provided variable results, indicating either a reduced expression or a compensatory increase in indexes of striatal 5-HT innervation. A recent study in MPTP-treated monkeys has suggested that a gradual increase
M.A. Cenci et al. / Parkinsonism and Related Disorders 15S3 (2009) S59–S63
in striatal 5-HT turnover (which may be due to increased serotonin innervation densities) may be involved in long-term motor recovery [31]. A relatively high density of serotonin fibers in the striatum may, however, also predispose to LID, as indicated by recent studies in the rat [13]. As to the role of BDNF, studies performed in 6-OHDA-lesioned rats have shown that chronic treatment with high doses of L-DOPA causes upregulation of BDNF in the corticostriatal pathway, and that this response is involved in the development of behavioural sensitization, although an implication of the serotonin system in the underlying mechanisms was not suspected [32]. The role of BDNF in human PD has thus far been addressed only in clinical genetic investigations. The studies performed so far have addressed the impact of a common single nucleotide polymorphism in the BDNF gene on the development specific symptoms. Methionine to valine substitution at codon 66 in the prodomain of BDNF (Val66Met) is a common polymorphism that has been associated with altered susceptibility to a variety of neuropsychiatric disorders (reviewed in [33]). This polymorphism has now been associated also with cognitive impairment in PD [34]. Furthermore, in a population-based cohort study performed in the United Kingdom, PD patients harboring “met” alleles were found to have a higher risk of developing dyskinesia early after initiating treatment with L-DOPA [5]. The mechanisms by which the Val66Met polymorphism predisposes to LID are unknown and counterintuitive, because the “met” allele would be expected to result in reduced activitydependent secretion of BDNF (reviewed in [33]). 5. Structural plasticity Activation of intracellular signaling pathways, gene and protein induction are rapid responses that cannot account for the virtually permanent predisposition to dyskinesia established by chronic L-DOPA treatment. This truly long-lasting form of behavioural plasticity is likely to rely on structural modifications of cells and circuits in the brain (Fig. 1). The first indications that chronic L-DOPA treatment promotes structural plasticity in the brain came from gene array studies using 6-OHDA-lesioned rats. In one of these studies, 6 months of L-DOPA administration in the drinking water was found to produce a prominent striatal upregulation of genes encoding growth factors, metalloproteinases and their inhibitors, and myelin-related proteins [35]. Another study compared the pattern of striatal mRNA expression between dyskinetic rats and non-dyskinetic cases following three weeks of L-DOPA treatment [36]. The most salient features of the gene expression profile associated with dyskinesia indicated increased
Fig. 1. Plastic responses to acute and chronic L-DOPA treatment in the striatum as revealed by studies in 6-OHDA-lesioned rodents. Each dose of L-DOPA acutely activates intracellular signaling pathways, transcriptional and synaptic responses in dopaminoceptive neurons, whereas repeated exposure to L-DOPA causes persistent molecular and structural adaptations involving both neurons and non-neuronal cells in the brain. This chart summarizes a vast literature that can be cited only partially in this article due to space limitations. Additional literature citations can be found at [4,7,10].
S61
transcriptional activity of GABAergic neurons, structural and synaptic plasticity, and altered calcium-dependent signaling. A very recent microarray study in 6-OHDA-lesioned rats provided a comparison between acute and chronic L-DOPA treatment [37]. Here, the L-DOPA dose was above threshold for the induction of dyskinesia in all animals. Acute and chronic L-DOPA treatments were found to regulate a common set of genes involved in signaltransduction, transcription, translation, exocytosis and synaptic transmission. However, an about 3-fold larger number of genes were altered after chronic compared to acute L-DOPA treatment, and many genes involved in neurite outgrowth, synaptogenesis and cell proliferation were specifically affected in the chronically L-DOPA-treated rats. Altogether, these independent studies point to an association between repeated exposure to L-DOPA and structural and synaptic remodeling in the striatum. The cellular features and functional significance of this remodeling process will have to be unveiled through hypothesis-driven approaches in future studies. From the limited data available today, it is however possible to suggest that the structural plasticity induced by L-DOPA affects not only striatal neurons, but also afferent fiber systems and nonneuronal cells.
6. Microvascular plasticity An emerging literature is revealing that functional and structural alterations of the brain microvessels accompany both the progression of PD and the development of LID. Post-mortem investigations on human parkinsonian brains have revealed morphological alterations of capillaries and increased numbers of endothelial cells in the substantia nigra [38,39]. The observed changes were regarded as a response to the neurodegenerative process in PD and a possible effect of DA replacement therapy was not suspected. Recent studies in 6-OHDA-lesioned rats have shown that chronic L-DOPA treatment induces endothelial proliferation in the striatum and its output structures (including the substantia nigra), and that this response is associated with an upregulation of immature endothelial markers and a downregulation of bloodbrain barrier (BBB) proteins. The magnitude of this angiogenic response is positively correlated with the severity of the dyskinesia induced by the treatment [40]. Antiparkinsonian drug treatments that stimulate motor activity in the absence of dyskinesia do not evoke this response, which depends on the activation of D1like DA receptors and ERK1/2 [17]. Angiogenesis can occur in the adult brain as a homeostatic response to locally increased metabolic demands, as seen in the primary motor cortex following prolonged exercise [41]. Because dyskinesia is believed to involve an increased energy expenditure in the basal ganglia [36], L-DOPAinduced angiogenesis may be viewed as a plastic response aimed at increasing oxygen and nutrient supply to the affected brain regions. However, the positive correlation between angiogenic activity and LID severity suggests that this response has a maladaptive value. The mechanisms by which microvascular plasticity predisposes to LID are as yet unclear. Because the passage of L-DOPA from blood to brain is critically limited by the BBB, the simplest possibility is that angiogenic microvessels create foci of high L-DOPA concentrations within the brain parenchyma. Similarly to the situation described in other neurological diseases [42], dysfunction of the BBB may also cause extravasation of blood constituents and local perturbations of ion homeostasis. It is presently unclear whether our findings can be generalized to other animal models of LID and to human PD patients. Ongoing studies in our laboratory are examining indices of angiogenesis and increased BBB permeability in post-mortem brains from PD patients with or without clinical records of LID. Results from these studies will soon become available.
S62
M.A. Cenci et al. / Parkinsonism and Related Disorders 15S3 (2009) S59–S63
7. Concluding remarks The term neuroplasticity refers to the brain’s ability to reorganize itself in response to inner or outer challenges. On a cellular level, brain plasticity involves functional and structural modifications of synapses, neurons, and non-neuronal cells. The brain’s “plasticity potential” conditions the capacity for functional recovery after brain damage and the response to neuropsychiatric treatment interventions. This has been clearly demonstrated to be the case for antidepressant pharmacotherapies (partially reviewed in [27,28]). The implications of neuroplasticity in the response to antiparkinsonian therapy are much less understood. Yet, a rapidly growing body of literature is showing that treatment with L-DOPA has pervasive, plasticity-promoting effects in the parkinsonian brain. It is tempting to speculate that treatmentinduced neuroplasticity underlies the enduring clinical benefit that has been observed for weeks after dopaminergic drug withdrawal in early PD [43]. In the advanced stages of the disease, L-DOPAinduced plasticity could, however, be viewed as a double-edged sword: while boosting trophic factor production and cellular defense mechanisms, it would also predispose to dyskinesia and other complications. A better understanding of the plasticity mechanisms recruited by dopaminergic pharmacotherapies, and of their functional significance, will provide a basis to design antiparkinsonian treatments that can improve cellular resilience without causing untoward effects. Acknowledgements The authors’ ongoing projects in this area are supported by grants from the Swedish Research Council, the Michael J. Fox Foundation for Parkinson’s Research, the Swedish Parkinson Foundation, and from the EU grant contract number 222918 (REPLACES) FP7 (Thematic priority HEALTH). Conflict of interests The authors declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. References 1. Grandas F, Galiano ML, Tabernero C. Risk factors for levodopa-induced dyskinesias in Parkinson’s disease. J Neurol 1999;246(12):1127–33. 2. Manson A, Schrag A. Levodopa-induced dyskinesias, the clinical problem: clinical features, incidence, risk factors, management and impact on quality of life. In: Bezard E, editor, Recent breakthroughs in basal ganglia research. New York: Nova Science Publishers; 2006. p. 369–80. 3. Linazasoro G. New ideas on the origin of L-dopa-induced dyskinesias: age, genes and neural plasticity. Trends Pharmacol Sci 2005;26(8):391–7. 4. Cenci MA, Lundblad M. Post- versus presynaptic plasticity in L-DOPA-induced dyskinesia. J Neurochem 2006;99(2):381–92. 5. Foltynie T, Cheeran B, Williams-Gray CH, Edwards MJ, Schneider SA, Weinberger D, et al. BDNF val66met influences time to onset of levodopa induced dyskinesia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2009;80(2):141–4. 6. Morgante F, Espay AJ, Gunraj C, Lang AE, Chen R. Motor cortex plasticity in Parkinson’s disease and levodopa-induced dyskinesias. Brain 2006;129(Pt 4): 1059–69. 7. Jenner P. Molecular mechanisms of L-DOPA-induced dyskinesia. Nat Rev Neurosci 2008;9(9):665–77. 8. Picconi B, Centonze D, Hakansson K, Bernardi G, Greengard P, Fisone G. Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nat Neurosci 2003;6:501–6. 9. Chase TN. Levodopa therapy: consequences of the nonphysiologic replacement of dopamine. Neurology 1998;50(5 Suppl 5):S17–25. 10. Cenci MA, Lindgren HS. Advances in understanding L-DOPA-induced dyskinesia. Curr Opin Neurobiol 2007;17(6):665–71.
11. Lee J, Zhu WM, Stanic D, Finkelstein DI, Horne MH, Henderson J, et al. Sprouting of dopamine terminals and altered dopamine release and uptake in Parkinsonian dyskinaesia. Brain 2008;131(Pt 6):1574–87. 12. Troiano AR, de la Fuente-Fernandez ´ R, Sossi V, Schulzer M, Mak E, Ruth TJ, et al. PET demonstrates reduced dopamine transporter expression in PD with dyskinesias. Neurology 2009;72(14):1211–6. 13. Rylander D, Strome E, Mela F, Mercanti G, Cenci MA. The severity of L-DOPAinduced dyskinesia in the rat is positively correlated with the density of striatal serotonin afferents. Parkinsonism Relat Disord 2007;13(Suppl 2):S90. 14. Tanaka H, Kannari K, Maeda T, Tomiyama M, Suda T, Matsunaga M. Role of serotonergic neurons in L-DOPA-derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats. Neuroreport 1999;10(3):631–4. 15. Carta M, Carlsson T, Kirik D, Bjorklund A. Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain 2007;130(Pt 7):1819–33. 16. Lindgren HS, Andersson DR, Lagerkvist S, Nissbrandt H, Cenci MA. L-DOPAinduced 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. J Neurochem 2009; under revision. 17. Lindgren HS, Ohlin KE, Cenci MA. Differential involvement of D1 and D2 dopamine receptors in L-DOPA-induced angiogenic activity in a rat model of Parkinson’s disease. Neuropsychopharmacology 2009;34:2477–88. 18. Rascol O, Nutt JG, Blin O, Goetz CG, Trugman JM, Soubrouillard C, et al. Induction by dopamine D1 receptor agonist ABT-431 of dyskinesia similar to levodopa in patients with Parkinson disease. Arch Neurol 2001;58(2):249–54. 19. Gerfen CR, Miyachi S, Paletzki R, Brown P. D1 dopamine receptor supersensitivity in the dopamine-depleted striatum results from a switch in the regulation of ERK1/2/MAP kinase. J Neurosci 2002;22(12):5042–54. 20. Sweatt JD. The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 2001;76:1–10. 21. Santini E, Valjent E, Usiello A, Carta M, Borgkvist A, Girault JA, et al. Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia. J Neurosci 2007;27(26):6995– 7005. 22. Westin JE, Vercammen L, Strome EM, Konradi C, Cenci MA. Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPAinduced dyskinesia and the role of dopamine D1 receptors. Biol Psychiatry 2007;62(7):800–10. 23. Ingham CA, Hood SH, Arbuthnott GW. Spine density on neostriatal neurones changes with 6-hydroxydopamine lesions and with age. Brain Res 1989;503(2): 334–8. 24. Ingham CA, Hood SH, van Maldegem B, Weenink A, Arbuthnott GW. Morphological changes in the rat neostriatum after unilateral 6-hydroxydopamine injections into the nigrostriatal pathway. Exp Brain Res 1993;93(1):17–27. 25. Zaja-Milatovic S, Milatovic D, Schantz AM, Zhang J, Montine KS, Samii A, et al. Dendritic degeneration in neostriatal medium spiny neurons in Parkinson disease. Neurology 2005;64(3):545–7. 26. Schuster S, Doudnikoff E, Rylander D, Berthet A, Aubert I, Ittrich C, et al. Antagonizing L-type Ca2+ channel reduces development of abnormal involuntary movement in the rat model of L-3,4-dihydroxyphenylalanineinduced dyskinesia. Biol Psychiatry 2009;65(6):518–26. 27. Martinowich K, Lu B. Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology 2008;33(1):73–83. 28. Mattson MP, Maudsley S, Martin B. BDNF and 5-HT: a dynamic duo in agerelated neuronal plasticity and neurodegenerative disorders. Trends Neurosci 2004;27(10):589–94. 29. Henningsson S, Borg J, Lundberg J, Bah J, Lindstrom M, Ryding E, et al. Genetic variation in brain-derived neurotrophic factor is associated with serotonin transporter but not serotonin-1A receptor availability in men. Biol Psychiatry 2009;66(5):477–85. 30. Kish SJ, Tong J, Hornykiewicz O, Rajput A, Chang LJ, Guttman M, et al. Preferential loss of serotonin markers in caudate versus putamen in Parkinson’s disease. Brain 2008;131(Pt 1):120–31. 31. Boulet S, Mounayar S, Poupard A, Bertrand A, Jan C, Pessiglione M, et al. Behavioral recovery in MPTP-treated monkeys: neurochemical mechanisms studied by intrastriatal microdialysis. J Neurosci 2008;28(38):9575–84. 32. Guillin O, Diaz J, Carroll P, Griffon N, Schwartz JC, Sokoloff P. BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 2001;411(6833):86–9. 33. Chen ZY, Bath K, McEwen B, Hempstead B, Lee F. Impact of genetic variant BDNF (Val66Met) on brain structure and function. Novartis Found Symp 2008; 289:180–8; discussion: 188–95. 34. Guerini FR, Beghi E, Riboldazzi G, Zangaglia R, Pianezzola C, Bono G, et al. BDNF Val66Met polymorphism is associated with cognitive impairment in Italian patients with Parkinson’s disease. Eur J Neurol 2009;16:1240–5. 35. Ferrario JE, I.R. Taravini, S. Mourlevat, A. Stefano, M.A. Delfino, R. Raisman-Vozari, et al. Differential gene expression induced by chronic levodopa treatment in the striatum of rats with lesions of the nigrostriatal system. J Neurochem 2004; 90(6):1348–58. 36. Konradi C, J.E. Westin, M. Carta, M.E. Eaton, K. Kuter, A. Dekundy, et al.
M.A. Cenci et al. / Parkinsonism and Related Disorders 15S3 (2009) S59–S63
Transcriptome analysis in a rat model of L-DOPA-induced dyskinesia. Neurobiol Dis 2004;17(2):219–36. 37. El Atifi-Borel M, V. Buggia-Prevot, N. Platet, A.L. Benabid, F. Berger, SgambatoFaure V. De novo and long-term L-Dopa induce both common and distinct striatal gene profiles in the hemiparkinsonian rat. Neurobiol Dis 2009;34(2): 340–50. 38. Farkas E, G.I. De Jong, R.A. de Vos, E.N. Jansen Steur, Luiten PG. Pathological features of cerebral cortical capillaries are doubled in Alzheimer’s disease and Parkinson’s disease. Acta Neuropathol 2000;100(4):395–402. 39. Faucheux BA, A.M. Bonnet, Y. Agid, Hirsch EC. Blood vessels change in the mesencephalon of patients with Parkinson’s disease. Lancet 1999;353(9157): 981–2.
S63
40. Westin JE, H.S. Lindgren, J. Gardi, J.R. Nyengaard, P. Brundin, P. Mohapel, et al. Endothelial proliferation and increased blood–brain barrier permeability in the basal ganglia in a rat model of 3,4-dihydroxyphenyl-L-alanine-induced dyskinesia. J Neurosci 2006;26(37):9448–61. 41. Swain RA, A.B. Harris, E.C. Wiener, M.V. Dutka, H.D. Morris, B.E. Theien, et al. Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat. Neuroscience 2003;117(4):1037–46. 42. Ivens S, D. Kaufer, L.P. Flores, I. Bechmann, D. Zumsteg, O. Tomkins, et al. TGFbeta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 2007;130(Pt 2):535–47. 43. Fahn S, D. Oakes, I. Shoulson, K. Kieburtz, A. Rudolph, A. Lang, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004;351:2498–508.
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Plastic effects of L-DOPA treatment in the basal ganglia and their relevance to the development of dyskinesia M. Angela Cenci*, K. Elisabet Ohlin, Daniella Rylander Basal Ganglia Pathophysiology Unit, Dept. Experimental Medical Science, Lund University, BMC F11, 221 84 Lund, Sweden
article info
summary
Keywords: Dopamine receptor D1 Extracellular signal-regulated kinases 1 and 2 ERK1/2 Angiogenesis 5-Hydroxytryptamine Serotonin transporter Dopamine transporter
The development of L-DOPA-induced dyskinesia (LID) is attributed to plastic responses triggered by dopamine (DA) receptor stimulation in the parkinsonian brain. This article reviews studies that have uncovered different levels of maladaptive plasticity in animal models of LID. Rats developing dyskinesia on chronic L-DOPA treatment show abnormal patterns of signaling pathway activation and synaptic plasticity in striatal neurons. In addition, these animals show a gene expression profile indicative of structural cellular plasticity, including pronounced upregulation of genes involved in extracellular matrix remodeling, neurite extension, synaptic vesicle trafficking, and endothelial and cellular proliferation. Structural changes of neurons and microvessels within the basal ganglia are currently being unraveled by detailed morphological analyses. The structural and functional adaptations induced by L-DOPA in the brain can be viewed as an attempt to meet increased metabolic demands and to boost cellular defense mechanisms. These homeostatic responses, however, also predispose to the appearance of dyskinesia and other complications during the course of the treatment. © 2009 Elsevier Ltd. All rights reserved.
1. Introduction L-DOPA remains the most efficacious drug to treat the signs and symptoms of Parkinson’s disease, but it causes dyskinesia (abnormal involuntary movements) in the majority of the patients. L-DOPA-induced dyskinesia (LID) has been reported to occur in about 10% of patients per year in the first seven years of treatment [1], but the reported incidence of LID varies greatly between studies and patient groups [2]. Some people exhibit severe dyskinesias very rapidly, whereas others do not develop this complication despite many years of L-DOPA treatment. A generally accepted view holds that the susceptibility to LID is determined by the brain’s “plasticity potential” [3]. According to this view, LID is an aberrant form of neuroplasticity that is triggered by the combined effects of DA denervation and pharmacological DA replacement. The gradual development and persistence of LID suggest that a disorder of brain plasticity is implicated in its pathophysiology. Once developed, LID is very difficult to reduce or reverse, it is promptly elicited by L-DOPA even after long periods of treatment discontinuation, it is induced also by nondyskinesiogenic drugs (e.g. long-acting DA agonists), and it can be precipitated by stress (partly reviewed in [4]). The brain’s “plasticity potential” varies among individuals depending on age and genetics, and this has been proposed as an explanation to the varying susceptibility to dyskinesia in PD [3]. The group at highest * Corresponding author. E-mail address: [email protected] (M.A. Cenci). 1353-8020/$ – see front matter © 2009 Elsevier Ltd. All rights reserved.
risk of developing LID are young-onset PD patients (see [2] for review), who are supposedly endowed with the greatest potential for neuroplasticity within the parkinsonian patient population. The time to onset of LID in PD is influenced by a functional polymorphism in the gene coding for brain-derived neurotrophic factor (BDNF) [5], which is a prime mediator of neuroplasticity in health and disease (see below). Furthermore, using a paired associative stimulation protocol, abnormal plastic responses of the motor cortex have been evidenced in PD patients affected by LID [6]. Because corticostriatal synapses play a pivotal role in movement selection, many authors have attributed LID to an aberrant plasticity of corticostriatal synapses (reviewed in [4,7]). Studies in acute brain slices from L-DOPA-treated rats have indeed revealed an abnormal form of corticostriatal synaptic plasticity in dyskinetic animals, consisting in a failure to reverse long-term potentiation (LTP) upon low-frequency stimulation of the cortical afferent pathway [8]. Despite all these strong indicia, questions on the “why, where, and what” of abnormal plasticity mechanisms in LID are still wideopen. The studies of corticostriatal synaptic plasticity thus far performed are neither exhaustive nor conclusive (in particular, a causal link between the observed abnormality and the occurrence of dyskinesia has not yet been demonstrated). Moreover, in addition to corticostriatal synapses, many types of cells and circuits within the basal ganglia show plastic changes in animal models of LID. By reviewing different levels of plastic alterations in LID, this article will provide a brief survey on a presently scattered, but rapidly growing area of investigation.
S60
M.A. Cenci et al. / Parkinsonism and Related Disorders 15S3 (2009) S59–S63
2. Presynaptic plasticity Large intermittent fluctuations in brain levels of DA have been classically attributed a prime causal role in LID [9]. These fluctuations would be due to the loss of nigrostriatal DA neurons, which inevitably causes L-DOPA to be taken up and decarboxylated by brain cells that lack DA storage capacity (reviewed in [4]). Recent studies in animal models of LID and human PD patients suggest that the extent of nigrostriatal DA lesion is not the only determinant of the large DA fluctuations induced by L-DOPA (reviewed in [10]). The increase in extracellular DA levels post L-DOPA administration would be exaggerated by a reduced expression or dysfunction of the DA transporter (DAT) in residual nigrostriatal terminals [11,12], and by a high density of serotonergic axon fibers in the striatum [13]. Serotonin neurons express the enzymes required to convert L-DOPA to DA, and have the ability to store DA in synaptic vesicles, thus protecting it from cytosolic degradation. However, the uptake and conversion of exogenous L-DOPA by serotonin neurons result in non-regulated DA efflux and defective clearance of extracellular DA. In 6-OHDA-lesioned rats, treatment with the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) attenuates the L-DOPA-induced increase in striatal extracellular DA levels by 80% [14] and completely abolishes LID [15]. Agonists of serotonin 5-HT1A and 5-HT1B receptors, which reduce transmitter release from serotonergic neurons, exert pronounced antidyskinetic effects in animal models of LID [15]. The same agents blunt the peak of extracellular DA levels following peripheral L-DOPA administration [16].
which have been evidenced at both the light and the electron microscopic levels. Studies using the Golgi silver-impregnation technique in rats with 6-hydroxydopamine (6-OHDA) lesions have shown that the loss of DA input is rapidly followed by a decrease in the number of dendritic spines in striatal medium-sized spiny neurons, and that this structural modification is virtually permanent [23,24]. Interestingly, post-mortem studies in human PD patients have revealed changes in striatal neuron morphology similar to those observed in the rat model [25]. Because the patients had been treated with L-DOPA for many years, these results suggest that pharmacological dopaminergic therapies do not normalize the dendritic structure of striatal neurons. The treatment’s inability to restore structural features of the nigrostriatal microcircuitry is attracting growing attention as a potential mechanism in LID [7], but our current understanding of this mechanism is, at best, rudimentary. Only one published study thus far has addressed the impact of denervation-induced spine pruning on the development of LID [26]. In this study, a treatment that completely prevented the lesion-induced spine loss (i.e. continuous administration of the L-type calcium channel blocker, isradipine) achieved a partial attenuation of LID in 6-OHDA-lesioned rats [26]. There is an obvious need for further investigations addressing the role of striatal dendritic abnormalities in the pathophysiology of LID. In addition to the spine loss that follows DA denervation, it will be important to examine superimposed changes in dendritic morphology that occur upon treatment with L-DOPA. 4. Plasticity of the serotonin system and involvement of BDNF
3. Denervation-induced postsynaptic plasticity in the striatum Presynaptic abnormalities in the handling of exogenous L-DOPA cannot alone account for LID. Indeed, dyskinesias indistinguishable from those induced by L-DOPA are evoked by direct DA receptor agonists in both animal models [17] and PD patients [18]. Like LID, DA agonist-induced dyskinesias only occur when the nigrostriatal DA pathway is severely damaged. This argues for a critical role of postsynaptic mechanisms in the predisposition to LID caused by DA denervation. In this context, two types of postsynaptic changes are attributed a particularly important role. The first is a denervation-dependent supersensitivity of DA D1 receptors, which is emerging as a critical determinant of LID in both rodent and non-human primate models of PD (partially reviewed in [10]). This supersensitivity is not dependent on an increased number of D1 receptors, but reflects aberrant signaltransduction mechanisms. Both canonical (cyclic AMP-dependent) and non-canonical pathways show pronounced activation in DAdenervated striatal neurons upon treatment with either D1 receptor agonists or L-DOPA. In a seminal study, Gerfen and collaborators showed that treatment with D1 receptor agonists induces mitogenactivated protein kinases (MAPK) in striatonigral neurons in the DAdenervated but not the intact striatum [19]. The MAPK signaling system was originally discovered as a critical regulator of cell division and differentiation, and was later found to be recruited in mature neurons by different types of extracellular stimuli inducing long-term synaptic and behavioral adaptations [20]. It was later found that treatment with L-DOPA induces a pronounced striatal activation of p44 MAPK and p42 MAPK (most commonly referred to as extracellular signal-regulated kinases 1 and 2, ERK1/2) specifically in animals that develop dyskinesia [21,22]. The striatal levels of phosphorylated (active) ERK1/2 correlate positively both with the abnormal involuntary movement scores, and with the expression of nuclear signaling markers, such as the activation of histone kinases and the upregulation of DFosB-like transcription factors [22]. In addition to receptor supersensitivity, DA denervation causes changes in dendritic and synaptic morphology in striatal neurons,
Serotonin (5-hydroxytryptamine, 5-HT) is produced by neurons in the brainstem raphe nuclei, which send widespread projections to cortical and subcortical brain regions, modulating a wide array of functions, including sensorimotor control, cognition and mood. A closer look at this neuronal system is highly warranted given its crucial role in the generation of LID (at least in animal models), and its potential implication in the cognitive and psychiatric problems afflicting PD patients. Serotonin neurons show both a high vulnerability to neurodegeneration and a high capacity for neuroplasticity, and these processes are heavily influenced by brain derived neurotrophic factor (BDNF). This neurotrophin can enhance 5-HT biosynthesis, upregulate 5-HT uptake, potentiate depolarization-induced 5-HT release, and modify the firing pattern of 5-HT neurons (partly reviewed in [27]). In addition, BDNF has growth-promoting effects on 5-HT axons. Conversely, the serotonergic system promotes the expression of BDNF via 5-HT 4,5,6 receptors, whose downstream signaling cascades positively regulate BDNF gene transcription [27]. Because of their tight functional interactions, BDNF and 5-HT have been defined as a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders [28]. There is growing evidence of synergism between the 5-HT system and BDNF in the genetic susceptibility to affective disorders and in the response to antidepressant treatment (reviewed in [27,29]). Plastic responses involving the “5-HT-BDNF duo” have just started to be investigated in PD. A recent post-mortem study in PD patients found that several 5-HT markers (i.e. the 5-HT transporter protein, the 5-HT biosynthetic enzyme tryptophan hydroxylase, and the levels of 5-HT and its metabolite) were decreased by 30–66% in both cognitive and sensorimotor striatal domains, without any evident relationship with the occurrence or absence of LID [30]. The loss of 5-HT markers was thus interpreted as being a consequence of the neurodegenerative process in PD. Studies of the 5-HT system in animal models of PD have, however, provided variable results, indicating either a reduced expression or a compensatory increase in indexes of striatal 5-HT innervation. A recent study in MPTP-treated monkeys has suggested that a gradual increase
M.A. Cenci et al. / Parkinsonism and Related Disorders 15S3 (2009) S59–S63
in striatal 5-HT turnover (which may be due to increased serotonin innervation densities) may be involved in long-term motor recovery [31]. A relatively high density of serotonin fibers in the striatum may, however, also predispose to LID, as indicated by recent studies in the rat [13]. As to the role of BDNF, studies performed in 6-OHDA-lesioned rats have shown that chronic treatment with high doses of L-DOPA causes upregulation of BDNF in the corticostriatal pathway, and that this response is involved in the development of behavioural sensitization, although an implication of the serotonin system in the underlying mechanisms was not suspected [32]. The role of BDNF in human PD has thus far been addressed only in clinical genetic investigations. The studies performed so far have addressed the impact of a common single nucleotide polymorphism in the BDNF gene on the development specific symptoms. Methionine to valine substitution at codon 66 in the prodomain of BDNF (Val66Met) is a common polymorphism that has been associated with altered susceptibility to a variety of neuropsychiatric disorders (reviewed in [33]). This polymorphism has now been associated also with cognitive impairment in PD [34]. Furthermore, in a population-based cohort study performed in the United Kingdom, PD patients harboring “met” alleles were found to have a higher risk of developing dyskinesia early after initiating treatment with L-DOPA [5]. The mechanisms by which the Val66Met polymorphism predisposes to LID are unknown and counterintuitive, because the “met” allele would be expected to result in reduced activitydependent secretion of BDNF (reviewed in [33]). 5. Structural plasticity Activation of intracellular signaling pathways, gene and protein induction are rapid responses that cannot account for the virtually permanent predisposition to dyskinesia established by chronic L-DOPA treatment. This truly long-lasting form of behavioural plasticity is likely to rely on structural modifications of cells and circuits in the brain (Fig. 1). The first indications that chronic L-DOPA treatment promotes structural plasticity in the brain came from gene array studies using 6-OHDA-lesioned rats. In one of these studies, 6 months of L-DOPA administration in the drinking water was found to produce a prominent striatal upregulation of genes encoding growth factors, metalloproteinases and their inhibitors, and myelin-related proteins [35]. Another study compared the pattern of striatal mRNA expression between dyskinetic rats and non-dyskinetic cases following three weeks of L-DOPA treatment [36]. The most salient features of the gene expression profile associated with dyskinesia indicated increased
Fig. 1. Plastic responses to acute and chronic L-DOPA treatment in the striatum as revealed by studies in 6-OHDA-lesioned rodents. Each dose of L-DOPA acutely activates intracellular signaling pathways, transcriptional and synaptic responses in dopaminoceptive neurons, whereas repeated exposure to L-DOPA causes persistent molecular and structural adaptations involving both neurons and non-neuronal cells in the brain. This chart summarizes a vast literature that can be cited only partially in this article due to space limitations. Additional literature citations can be found at [4,7,10].
S61
transcriptional activity of GABAergic neurons, structural and synaptic plasticity, and altered calcium-dependent signaling. A very recent microarray study in 6-OHDA-lesioned rats provided a comparison between acute and chronic L-DOPA treatment [37]. Here, the L-DOPA dose was above threshold for the induction of dyskinesia in all animals. Acute and chronic L-DOPA treatments were found to regulate a common set of genes involved in signaltransduction, transcription, translation, exocytosis and synaptic transmission. However, an about 3-fold larger number of genes were altered after chronic compared to acute L-DOPA treatment, and many genes involved in neurite outgrowth, synaptogenesis and cell proliferation were specifically affected in the chronically L-DOPA-treated rats. Altogether, these independent studies point to an association between repeated exposure to L-DOPA and structural and synaptic remodeling in the striatum. The cellular features and functional significance of this remodeling process will have to be unveiled through hypothesis-driven approaches in future studies. From the limited data available today, it is however possible to suggest that the structural plasticity induced by L-DOPA affects not only striatal neurons, but also afferent fiber systems and nonneuronal cells.
6. Microvascular plasticity An emerging literature is revealing that functional and structural alterations of the brain microvessels accompany both the progression of PD and the development of LID. Post-mortem investigations on human parkinsonian brains have revealed morphological alterations of capillaries and increased numbers of endothelial cells in the substantia nigra [38,39]. The observed changes were regarded as a response to the neurodegenerative process in PD and a possible effect of DA replacement therapy was not suspected. Recent studies in 6-OHDA-lesioned rats have shown that chronic L-DOPA treatment induces endothelial proliferation in the striatum and its output structures (including the substantia nigra), and that this response is associated with an upregulation of immature endothelial markers and a downregulation of bloodbrain barrier (BBB) proteins. The magnitude of this angiogenic response is positively correlated with the severity of the dyskinesia induced by the treatment [40]. Antiparkinsonian drug treatments that stimulate motor activity in the absence of dyskinesia do not evoke this response, which depends on the activation of D1like DA receptors and ERK1/2 [17]. Angiogenesis can occur in the adult brain as a homeostatic response to locally increased metabolic demands, as seen in the primary motor cortex following prolonged exercise [41]. Because dyskinesia is believed to involve an increased energy expenditure in the basal ganglia [36], L-DOPAinduced angiogenesis may be viewed as a plastic response aimed at increasing oxygen and nutrient supply to the affected brain regions. However, the positive correlation between angiogenic activity and LID severity suggests that this response has a maladaptive value. The mechanisms by which microvascular plasticity predisposes to LID are as yet unclear. Because the passage of L-DOPA from blood to brain is critically limited by the BBB, the simplest possibility is that angiogenic microvessels create foci of high L-DOPA concentrations within the brain parenchyma. Similarly to the situation described in other neurological diseases [42], dysfunction of the BBB may also cause extravasation of blood constituents and local perturbations of ion homeostasis. It is presently unclear whether our findings can be generalized to other animal models of LID and to human PD patients. Ongoing studies in our laboratory are examining indices of angiogenesis and increased BBB permeability in post-mortem brains from PD patients with or without clinical records of LID. Results from these studies will soon become available.
S62
M.A. Cenci et al. / Parkinsonism and Related Disorders 15S3 (2009) S59–S63
7. Concluding remarks The term neuroplasticity refers to the brain’s ability to reorganize itself in response to inner or outer challenges. On a cellular level, brain plasticity involves functional and structural modifications of synapses, neurons, and non-neuronal cells. The brain’s “plasticity potential” conditions the capacity for functional recovery after brain damage and the response to neuropsychiatric treatment interventions. This has been clearly demonstrated to be the case for antidepressant pharmacotherapies (partially reviewed in [27,28]). The implications of neuroplasticity in the response to antiparkinsonian therapy are much less understood. Yet, a rapidly growing body of literature is showing that treatment with L-DOPA has pervasive, plasticity-promoting effects in the parkinsonian brain. It is tempting to speculate that treatmentinduced neuroplasticity underlies the enduring clinical benefit that has been observed for weeks after dopaminergic drug withdrawal in early PD [43]. In the advanced stages of the disease, L-DOPAinduced plasticity could, however, be viewed as a double-edged sword: while boosting trophic factor production and cellular defense mechanisms, it would also predispose to dyskinesia and other complications. A better understanding of the plasticity mechanisms recruited by dopaminergic pharmacotherapies, and of their functional significance, will provide a basis to design antiparkinsonian treatments that can improve cellular resilience without causing untoward effects. Acknowledgements The authors’ ongoing projects in this area are supported by grants from the Swedish Research Council, the Michael J. Fox Foundation for Parkinson’s Research, the Swedish Parkinson Foundation, and from the EU grant contract number 222918 (REPLACES) FP7 (Thematic priority HEALTH). Conflict of interests The authors declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. References 1. Grandas F, Galiano ML, Tabernero C. Risk factors for levodopa-induced dyskinesias in Parkinson’s disease. J Neurol 1999;246(12):1127–33. 2. Manson A, Schrag A. Levodopa-induced dyskinesias, the clinical problem: clinical features, incidence, risk factors, management and impact on quality of life. In: Bezard E, editor, Recent breakthroughs in basal ganglia research. New York: Nova Science Publishers; 2006. p. 369–80. 3. Linazasoro G. New ideas on the origin of L-dopa-induced dyskinesias: age, genes and neural plasticity. Trends Pharmacol Sci 2005;26(8):391–7. 4. Cenci MA, Lundblad M. Post- versus presynaptic plasticity in L-DOPA-induced dyskinesia. J Neurochem 2006;99(2):381–92. 5. Foltynie T, Cheeran B, Williams-Gray CH, Edwards MJ, Schneider SA, Weinberger D, et al. BDNF val66met influences time to onset of levodopa induced dyskinesia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2009;80(2):141–4. 6. Morgante F, Espay AJ, Gunraj C, Lang AE, Chen R. Motor cortex plasticity in Parkinson’s disease and levodopa-induced dyskinesias. Brain 2006;129(Pt 4): 1059–69. 7. Jenner P. Molecular mechanisms of L-DOPA-induced dyskinesia. Nat Rev Neurosci 2008;9(9):665–77. 8. Picconi B, Centonze D, Hakansson K, Bernardi G, Greengard P, Fisone G. Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nat Neurosci 2003;6:501–6. 9. Chase TN. Levodopa therapy: consequences of the nonphysiologic replacement of dopamine. Neurology 1998;50(5 Suppl 5):S17–25. 10. Cenci MA, Lindgren HS. Advances in understanding L-DOPA-induced dyskinesia. Curr Opin Neurobiol 2007;17(6):665–71.
11. Lee J, Zhu WM, Stanic D, Finkelstein DI, Horne MH, Henderson J, et al. Sprouting of dopamine terminals and altered dopamine release and uptake in Parkinsonian dyskinaesia. Brain 2008;131(Pt 6):1574–87. 12. Troiano AR, de la Fuente-Fernandez ´ R, Sossi V, Schulzer M, Mak E, Ruth TJ, et al. PET demonstrates reduced dopamine transporter expression in PD with dyskinesias. Neurology 2009;72(14):1211–6. 13. Rylander D, Strome E, Mela F, Mercanti G, Cenci MA. The severity of L-DOPAinduced dyskinesia in the rat is positively correlated with the density of striatal serotonin afferents. Parkinsonism Relat Disord 2007;13(Suppl 2):S90. 14. Tanaka H, Kannari K, Maeda T, Tomiyama M, Suda T, Matsunaga M. Role of serotonergic neurons in L-DOPA-derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats. Neuroreport 1999;10(3):631–4. 15. Carta M, Carlsson T, Kirik D, Bjorklund A. Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain 2007;130(Pt 7):1819–33. 16. Lindgren HS, Andersson DR, Lagerkvist S, Nissbrandt H, Cenci MA. L-DOPAinduced 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. J Neurochem 2009; under revision. 17. Lindgren HS, Ohlin KE, Cenci MA. Differential involvement of D1 and D2 dopamine receptors in L-DOPA-induced angiogenic activity in a rat model of Parkinson’s disease. Neuropsychopharmacology 2009;34:2477–88. 18. Rascol O, Nutt JG, Blin O, Goetz CG, Trugman JM, Soubrouillard C, et al. Induction by dopamine D1 receptor agonist ABT-431 of dyskinesia similar to levodopa in patients with Parkinson disease. Arch Neurol 2001;58(2):249–54. 19. Gerfen CR, Miyachi S, Paletzki R, Brown P. D1 dopamine receptor supersensitivity in the dopamine-depleted striatum results from a switch in the regulation of ERK1/2/MAP kinase. J Neurosci 2002;22(12):5042–54. 20. Sweatt JD. The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 2001;76:1–10. 21. Santini E, Valjent E, Usiello A, Carta M, Borgkvist A, Girault JA, et al. Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia. J Neurosci 2007;27(26):6995– 7005. 22. Westin JE, Vercammen L, Strome EM, Konradi C, Cenci MA. Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPAinduced dyskinesia and the role of dopamine D1 receptors. Biol Psychiatry 2007;62(7):800–10. 23. Ingham CA, Hood SH, Arbuthnott GW. Spine density on neostriatal neurones changes with 6-hydroxydopamine lesions and with age. Brain Res 1989;503(2): 334–8. 24. Ingham CA, Hood SH, van Maldegem B, Weenink A, Arbuthnott GW. Morphological changes in the rat neostriatum after unilateral 6-hydroxydopamine injections into the nigrostriatal pathway. Exp Brain Res 1993;93(1):17–27. 25. Zaja-Milatovic S, Milatovic D, Schantz AM, Zhang J, Montine KS, Samii A, et al. Dendritic degeneration in neostriatal medium spiny neurons in Parkinson disease. Neurology 2005;64(3):545–7. 26. Schuster S, Doudnikoff E, Rylander D, Berthet A, Aubert I, Ittrich C, et al. Antagonizing L-type Ca2+ channel reduces development of abnormal involuntary movement in the rat model of L-3,4-dihydroxyphenylalanineinduced dyskinesia. Biol Psychiatry 2009;65(6):518–26. 27. Martinowich K, Lu B. Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology 2008;33(1):73–83. 28. Mattson MP, Maudsley S, Martin B. BDNF and 5-HT: a dynamic duo in agerelated neuronal plasticity and neurodegenerative disorders. Trends Neurosci 2004;27(10):589–94. 29. Henningsson S, Borg J, Lundberg J, Bah J, Lindstrom M, Ryding E, et al. Genetic variation in brain-derived neurotrophic factor is associated with serotonin transporter but not serotonin-1A receptor availability in men. Biol Psychiatry 2009;66(5):477–85. 30. Kish SJ, Tong J, Hornykiewicz O, Rajput A, Chang LJ, Guttman M, et al. Preferential loss of serotonin markers in caudate versus putamen in Parkinson’s disease. Brain 2008;131(Pt 1):120–31. 31. Boulet S, Mounayar S, Poupard A, Bertrand A, Jan C, Pessiglione M, et al. Behavioral recovery in MPTP-treated monkeys: neurochemical mechanisms studied by intrastriatal microdialysis. J Neurosci 2008;28(38):9575–84. 32. Guillin O, Diaz J, Carroll P, Griffon N, Schwartz JC, Sokoloff P. BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 2001;411(6833):86–9. 33. Chen ZY, Bath K, McEwen B, Hempstead B, Lee F. Impact of genetic variant BDNF (Val66Met) on brain structure and function. Novartis Found Symp 2008; 289:180–8; discussion: 188–95. 34. Guerini FR, Beghi E, Riboldazzi G, Zangaglia R, Pianezzola C, Bono G, et al. BDNF Val66Met polymorphism is associated with cognitive impairment in Italian patients with Parkinson’s disease. Eur J Neurol 2009;16:1240–5. 35. Ferrario JE, I.R. Taravini, S. Mourlevat, A. Stefano, M.A. Delfino, R. Raisman-Vozari, et al. Differential gene expression induced by chronic levodopa treatment in the striatum of rats with lesions of the nigrostriatal system. J Neurochem 2004; 90(6):1348–58. 36. Konradi C, J.E. Westin, M. Carta, M.E. Eaton, K. Kuter, A. Dekundy, et al.
M.A. Cenci et al. / Parkinsonism and Related Disorders 15S3 (2009) S59–S63
Transcriptome analysis in a rat model of L-DOPA-induced dyskinesia. Neurobiol Dis 2004;17(2):219–36. 37. El Atifi-Borel M, V. Buggia-Prevot, N. Platet, A.L. Benabid, F. Berger, SgambatoFaure V. De novo and long-term L-Dopa induce both common and distinct striatal gene profiles in the hemiparkinsonian rat. Neurobiol Dis 2009;34(2): 340–50. 38. Farkas E, G.I. De Jong, R.A. de Vos, E.N. Jansen Steur, Luiten PG. Pathological features of cerebral cortical capillaries are doubled in Alzheimer’s disease and Parkinson’s disease. Acta Neuropathol 2000;100(4):395–402. 39. Faucheux BA, A.M. Bonnet, Y. Agid, Hirsch EC. Blood vessels change in the mesencephalon of patients with Parkinson’s disease. Lancet 1999;353(9157): 981–2.
S63
40. Westin JE, H.S. Lindgren, J. Gardi, J.R. Nyengaard, P. Brundin, P. Mohapel, et al. Endothelial proliferation and increased blood–brain barrier permeability in the basal ganglia in a rat model of 3,4-dihydroxyphenyl-L-alanine-induced dyskinesia. J Neurosci 2006;26(37):9448–61. 41. Swain RA, A.B. Harris, E.C. Wiener, M.V. Dutka, H.D. Morris, B.E. Theien, et al. Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat. Neuroscience 2003;117(4):1037–46. 42. Ivens S, D. Kaufer, L.P. Flores, I. Bechmann, D. Zumsteg, O. Tomkins, et al. TGFbeta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 2007;130(Pt 2):535–47. 43. Fahn S, D. Oakes, I. Shoulson, K. Kieburtz, A. Rudolph, A. Lang, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004;351:2498–508.