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Effect of locus coeruleus denervation on levodopa-induced motor fluctuations in hemiparkinsonian rats

  • Parkinson's Disease and Allied Conditions - Original Article
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Abstract

Parkinson’s disease (PD) is characterized not only by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) but also by a degeneration of locus coeruleus (LC) noradrenergic neurons. It has been suggested that deficient LC noradrenergic mechanisms might play a critical role in symptomatology and in the progression of PD. However, the effect of LC depletion on levodopa-induced motor complications, such as the motor fluctuations, is still unknown. Male Sprague–Dawley rats received 50 mg/kg intraperitoneal (i.p.) of [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] (DSP-4) or saline 7 days before the day of 6-hydroxydopamine (6-OHDA, 8 μg) administration in the medial forebrain bundle. Four weeks later, animals were treated with levodopa (25 mg/kg with benserazide, twice at day, i.p.) for 22 days. Rotational behavior was measured on days 1 and 22 of levodopa administration. Tyrosine hydroxylase (TH) immunohistochemistry was performed to evaluate the neurodegeneration in the SNc and LC. Striatal dopamine transporter (DAT) immunohistochemistry was performed to evaluate DA depletion. As expected, levodopa administration decreased the duration of the motor response in the vehicle-pretreated group (P < 0.01). A potentiation of levodopa-induced shortening in the duration of motor response was not achieved after LC depletion since no significant differences were observed in the duration of rotational behavior between these two groups on day 22. In addition, LC depletion did not potentiate either the total number of rotations or the maximal peak of rotation induced by levodopa treatment. These results suggest that LC depletion might not be involved in the pathophysiology of levodopa-induced motor fluctuations.

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References

  • Anden N, Grabowska M (1976) Pharmacological evidence for a stimulation of dopamine neurons by noradrenaline neurons in the brain. Eur J Pharmacol 39:275–282

    Article  PubMed  CAS  Google Scholar 

  • Archer T, Ogren SO, Johansson G, Ross SB (1982) DSP-4 induced two-active avoidance impairment in rats: involvement of central and not peripheral noradrenaline depletion. Psychopharmacology 76:303–309

    Article  PubMed  CAS  Google Scholar 

  • Archer T, Fredriksson A (2000) Effects of clonidine and alpha-adrenoreceptor antagonists on motor activity in DSP-4 treated mice: dose-, time- and parameter-dependency. Neurotox Res 4:235–247

    Google Scholar 

  • Belujon P, Bezard E, Taupignon A, Bioulac B, Benazzouz A (2007) Noradrenergic modulation of subthalamic nucleus activity: behavioral and electrophysiological evidence in intact and 6-hydroxydopamine-lesioned rats. J Neurosci 27:9595–9606

    Article  PubMed  CAS  Google Scholar 

  • Bing G, Zhang Y, Watanabe T, McEven BS, Stone EA (1994) Locus coeruleus lesions potentiate neurotoxic effects of MPTP in dopaminergic neurons of the substantia nigra. Brain Res 668:161–165

    Article  Google Scholar 

  • Canteras NS, Shammah-Lagnado SJ, Silva BA, Ricardo JA (1990) Afferent connections of the subthalamic nucleus: a combined retrograde and anterograde horseradish peroxidase study in the rat. Brain Res 513:43–59

    Article  PubMed  CAS  Google Scholar 

  • Chopin P, Colpaert FC, Marien M (1999) Effects of alpha-2 adrenoreceptor agonists and antagonists on circling behavior in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway. J Pharmacol Exp Ther 288:798–804

    PubMed  CAS  Google Scholar 

  • Collingridge GL, James TA (1979) Neurochemical and electrophysiological evidence for a projection from the locus coeruleus to the substantia nigra. J Physiol 290:44

    Google Scholar 

  • DeLong MR (1990) Primate models of movement disorders of basal ganglia origin. Trends Neurosci 13:281–285

    Article  PubMed  CAS  Google Scholar 

  • Del Tredici K, Rüb U, De Vos RA, Bohl JR, Braak H (2002) Where does Parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 61:413–426

    PubMed  Google Scholar 

  • Ehringer H, Hornykiewicz O (1960) Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system. Klin Wochenschr 38:1236–1239

    Article  PubMed  CAS  Google Scholar 

  • Engber TM, Papa SM, Boldry RC, Chase TN (1994) NMDA receptor blockade reverses motor response alterations induced by levodopa. Neuroreport 5:2586–2588

    Article  PubMed  CAS  Google Scholar 

  • Fornai F, Bassi L, Torracca MT, Scalori V, Corsini GU (1995) Norepinephrine loss exacerbates methamphetamine-induced striatal dopamine depletion in mice. Eur J Pharmacol 283:99–102

    Article  PubMed  CAS  Google Scholar 

  • Fornai F, Bassi L, Torracca MT, Alessandri MG, Scalori V, Corsini GU (1996) Region-and neurotransmitter-dependent species and strain differences in DSP-4-induced monoamine depletion in rodents. Neurodegeneration 5:241–249

    Article  PubMed  CAS  Google Scholar 

  • Fornai F, Alessandri MG, Torracca MT, Bassi L, Corsini GU (1997) Effects of noradrenergic lesions on MPTP/MPP+ kinetics and MPTP-induced nigrostriatal dopamine depletion. J Pharmacol Exp Ther 283:100–107

    PubMed  CAS  Google Scholar 

  • Fornai F, di Poggio AB, Pellegrini A, Ruggieri S, Paprelli A (2007) Noradrenaline in Parinson’s disease progression to current therapeutics. Curr Med Chem 14:1330–1334

    Google Scholar 

  • Forno LS (1996) Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol 55:259–272

    Article  PubMed  CAS  Google Scholar 

  • Fritschy JM, Grzanna R (1989) Immunohistochemical analysis of the neurotoxic effects of DSP-4 identifies two populations of noradrenergic axon terminals. Neuroscience 30:191–197

    Article  Google Scholar 

  • Gesi M, Soldani P, Giorgi FS, Santiami A, Bonaccorsi I, Fornai F (2000) The role of the locus coeruleus in the development of Parkinson’s disease. Neurosci Biobehav Rev 24:655–668

    Article  PubMed  CAS  Google Scholar 

  • Grenhoff J, Nisell M, Ferré S, Aston-Jones G, Svensson TH (1993) Noradrenergic modulation of midbrain dopamine cell firing elicited by stimulation of the locus coeruleus in the rat. J Neural Transm Gen Sect 93:11–25

    Article  PubMed  CAS  Google Scholar 

  • Hornykiewicz O, Kish SJ (1987) Biochemical pathophysiology of Parkinson’s disease. Adv Neurol 45:19–34

    PubMed  CAS  Google Scholar 

  • Hornykiewicz O, Pifl C (1994) The validity of the MPTP primate model from neurochemical pathology of idiopathic Parkinson’s disease. In: Briley M, Marien M (eds) Noradrenergic mechanisms in Parkinson’s disease. CRC Press, Boca Raton, pp 59–71

    Google Scholar 

  • Hudson AL, Robinson ES, Lalies MD, Tyacke RJ, Jackson HC, Nutt DJ (1999) In vitro and in vivo approaches to the characterization of the alpha2-adrenoreceptor. J Auton Pharmacol 19:311–320

    Article  PubMed  CAS  Google Scholar 

  • Jones BE, Moore RY (1977) Ascending projections of the locus coeruleus in the rat. II. Autoradiographic study. Brain Res 127:25–53

    PubMed  CAS  Google Scholar 

  • Jones BE, Yang TZ (1985) The afferent projections from the reticular formation and the locus coeruleus studied by anterograde and retrograde axonal transport in the rat. J Comp Neurol 242:56–92

    Article  PubMed  CAS  Google Scholar 

  • Kitada T, Asakawa S, Hattori N, Matsumune H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608

    Article  PubMed  CAS  Google Scholar 

  • Kostic VS, Marinkovic J, Svetel M, Stefanova E, Przedborski S (2002) The effect of stage of Parkinson’s disease at the onset of levodopa therapy on development of motor complications. Eur J Neurol 9:9–14

    Article  PubMed  CAS  Google Scholar 

  • Lategan AJ, Marien MR, Coalpaert FC (1990) Effects of locus coeruleus lesions on the release of endogenous dopamine in the rat nucleus accumbens and caudate nucleus as determined by intracerebral microdialysis. Brain Res 523:134–138

    Article  PubMed  CAS  Google Scholar 

  • Lategan AJ, Marien MR, Colpaert FC (1992) Suppression of nigrostriatal and mesolimbic dopamine release in vivo following noradrenaline depletion by DSP-4: a microdialysis study. Life Sci 50:995–999

    Article  PubMed  CAS  Google Scholar 

  • Marien M, Briley M, Colpaert E (1993) Noradrenaline depletion exacerbates MPTP-induced striatal dopamine loss in mice. Eur J Pharmacol 236:487–489

    Article  PubMed  CAS  Google Scholar 

  • Marien M, Lategan A, Colpaert F (1994) Noradrenergic control of striatal dopamine. In: Briley M, Marien M (eds) Noradrenergic mechanisms in Parkinson’s disease. CRC Press, Boca Raton, pp 127–138

    Google Scholar 

  • Marien MR, Colpaert FC, Rosenquist AC (2004) Noradrenergic mechanisms in neurodegenerative diseases: a theory. Brain Res Rev 45:38–78

    Article  PubMed  CAS  Google Scholar 

  • Mason ST, Fibiger HC (1979) Regional topography within noradrenergic locus coeruleus as revealed by retrograde transport of horseradish peroxidase. J Comp Neurol 187:703–724

    Article  PubMed  CAS  Google Scholar 

  • Mavridis M, Degryse AD, Lategan AJ, Marien MR, Colapert FC (1991) Effect of locus coeruleus lesions on parkinsonian signs, striatal dopamine and substantia nigra cell loss after 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine in monkeys: a possible role for the locus coeruleus in the progression of Parkinson’s disease. Neuroscience 41:507–523

    Article  PubMed  CAS  Google Scholar 

  • Narabayashi H (1983) Pharmacological basis of akinesia in Parkinson’s disease. J Neural Transm Suppl 19:143–151

    PubMed  CAS  Google Scholar 

  • Nishi K, Kondo T, Narabayashi H (1991) Destruction of norepinephrine terminals in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated mice reduces locomotor activity induced by l-Dopa. Neurosci Lett 123:244–247

    Article  PubMed  CAS  Google Scholar 

  • Nutt JG, Holford NH (1996) The response to levodopa in Parkinson’s disease imposing pharmacological law and order. Ann Neurol 39:561–573

    Article  PubMed  CAS  Google Scholar 

  • Nutt DJ, Lalies M, Hudson A (1994) The effects of alpha-2-adrenoreceptor antagonists on extracellular dopamine concentrations in the rat striatum. In: Colpaert F, Briley M (eds) Noradrenergic mechanisms in Parkinson’s disease. Academic Press, New York, pp 159–172

    Google Scholar 

  • Obeso JA, Olanow CW, Nutt JG (2000) Levodopa motor complications in Parkinson’s disease. Trends Neurosci 23(10 Suppl):S8–S19

    Article  PubMed  CAS  Google Scholar 

  • Obeso JA, Rodríguez-Oroz MC, Marin C, Alonso F, Zamarbide I, Lanciego JL, Rodríguez-Díaz M (2004) The origin of motor fluctuations in Parkinson’s disease: importance of dopaminergic innervation and basal ganglia circuits. Neurology 62(1 Suppl 1):S17–S30

    PubMed  CAS  Google Scholar 

  • Olanow CW, Obeso JA, Stocchi F (2006) Continuous dopamine-receptor treatment of Parkinson’s disease: scientific rationale and clinical implications. Lancet Neurol 5:677–687

    Article  PubMed  CAS  Google Scholar 

  • Papa SM, Engber TM, Kask AM, Chase TN (1994) Motor fluctuations in levodopa-treated parkinsonian rats: relation to lesion extent and treatment duration. Brain Res 662:69–74

    Article  PubMed  CAS  Google Scholar 

  • Parent A, Hazrati LN (1995) Functional anatomy of the basal ganglia. II. The place of subthalamic nucleus and external pallidum in basal ganglia circuitry. Brain Res Brain Res Rev 20:128–154

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C. (1986) The rat brain in stereotaxic coordinates. Academic Press, New York

    Google Scholar 

  • Pérez V, Sosti V, Rubio A, Barbanoj M, Rodríguez-Álvarez J, Kulisevsky J (2007) Modulation of the motor response to dopaminergic drugs in a parkinsonian model of combined dopaminergic and noradrenergic degeneration. Eur J Pharmacol 576:83–90

    Article  PubMed  CAS  Google Scholar 

  • Pifl C, Schingnitz G, Hornykiewicz O (1991) Effect of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine on the regional distribution of brain monoamines in the rhesus monkey. Neuroscience 44:591–605

    Article  PubMed  CAS  Google Scholar 

  • Rommelfanger KS, Weinshenker D (2007) Norepimephrine: the redheaded stepchild of Parkinson’s disease. Biochem Pharmacol 74:177–190

    Article  PubMed  CAS  Google Scholar 

  • Rommelfanger KS, Edwards GL, Freeman KG, Liles LC, Miller GW, Weinshenker D (2007) Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice. Proc Natl Acad Sci USA 104:13804–13809

    Article  PubMed  CAS  Google Scholar 

  • Srinivasan J, Schmidt WJ (2003) Potentiation of parkinsonian symptoms by depletion of locus coeruleus noradrenaline in 6-hydroxydopamine-induced partial degeneration of substantia nigra in rats. Eur J Neurosci 17:2586–2592

    Article  PubMed  CAS  Google Scholar 

  • Srinivasan J, Schmidt WJ (2004) Functional recovery of locus coeruleus noradrenergic neurons after DSP-4 lesion: effects on dopamine levels and neuroleptic induced-parkinsonian symptoms in rats. J Neural Transm 111:13–26

    Article  PubMed  CAS  Google Scholar 

  • Thomas B, von Coelln R, Mandir AS, Trinkaus DB, Farah MH, Lim KL, Calingasan NY, Beal MF, Dawson VL, Dawson TM (2007) MPTP and DSP-4 susceptibility of substantia nigra and locus coeruleus catecholaminergic neurons in mice is independent of parkin activity. Neurobiol Dis 26:312–322

    Article  PubMed  CAS  Google Scholar 

  • Zarow C, Lyness SA, Mortimer JA, Chui HC (2007) Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson’s disease. Arch Neurol 60:337–341

    Article  Google Scholar 

  • Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM (2000) Parkin functions as an E2-dependent ubiquitin–protein ligase and promotes the degradation of the synpatic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci USA 97:13354–13359

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by a grant from the Ministerio de Sanidad y Consumo (FIS 05/0094). Esther Aguilar was partially financed by the program: Ayudas para Contratos de Apoyo a la Investigación en el Sistema Nacional de Salud from the Ministerio de Sanidad y Consumo of Spanish Government. Mercè Bonastre was financed by Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.

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Authors and Affiliations

  1. Laboratori de Neurologia Experimental, Servei de Neurologia, Villarroel 170, 08036, Barcelona, Spain

    C. Marin, E. Aguilar & M. Bonastre

  2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain

    C. Marin

  3. Laboratori de Neurologia Experimental, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Catalonia, Barcelona, Spain

    C. Marin, E. Aguilar & M. Bonastre

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  1. C. Marin
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Correspondence to C. Marin.

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Marin, C., Aguilar, E. & Bonastre, M. Effect of locus coeruleus denervation on levodopa-induced motor fluctuations in hemiparkinsonian rats. J Neural Transm 115, 1133–1139 (2008). https://doi.org/10.1007/s00702-008-0060-5

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  • DOI: https://doi.org/10.1007/s00702-008-0060-5

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