Globus pallidus, but not entopeduncular nucleus, 6-OHDA-induced lesion attenuates L-Dopa-induced dyskinesia in the rat model of Parkinson's disease

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Highlights

  • Extrastriatal dopaminergic systems have a relevant role in the development of L-Dopa-induced dyskinesias (LIDs).

  • External and internal pallidal Daergic innervation differentially contributes to the development of LIDs.

  • Pallidal dopaminergic activity has a key role in LIDs

  • Entopeduncular nucleus dopaminergic activity is not related with the development of LIDs

Abstract

Although extrastriatal dopaminergic (DAergic) systems are being recognized as contributors to Parkinson's disease (PD) pathophysiology, the role of extrastriatal DA depletion in L-Dopa-induced dyskinesia (LID) is still unknown. In view of the physiologic actions of DA on pallidal neuronal activity and the effects on motor behavior of local injection of DA drugs, the loss of the external (GPe, GP in rodents) and internal (GPi, entopeduncular nucleus (EP) in rodents) pallidal DAergic innervation might differentially contribute to LID. A role of pallidal serotonergic (SER) terminals in LID has been highlighted, however, the effect of DAergic innervation is unknown.

We investigated the role of DAergic pallidal depletion on LID. Rats were distributed in groups which were concomitantly lesioned with 6-OHDA or vehicle (sham) in the GP, or EP, and in the medial forebrain bundle (MFB) as follows: a) MFB-sham+GP-sham, b) MFB-sham+GP-lesion, c) MFB-lesion+GP-sham, d) MFB-lesion+GP-lesion, e) MFB-sham+EP-sham, f) MFB-sham+EP-lesion, g) MFB-lesion+EP-sham, and h) MFB-lesion+EP-lesion. Four weeks later, animals were treated with L-Dopa (6 mg/kg) twice daily for 22 days.. Immunohistochemical studies were performed in order to investigate the changes in pallidal SER and serotonin transporter (SERT) levels.

GP, but not EP, DAergic denervation attenuated LID in rats with a concomitant MFB lesion (p < 0.01). No differences were found in GP SERT expression between groups of animals developing or not LID.

These results provide evidence of the relevance of GP DAergic innervation in LID. The conversion of levodopa to DA in GP serotonergic nerve fibers appears not to be the major mechanism underlying LID.

Introduction

As a pathological hallmark of Parkinson's disease (PD), the nigrostriatal dopaminergic (DAergic) projection has been widely studied (Burke and O'Malley, 2013; Surmeier, 2018), however, less attention has been paid to the contribution of the extra-striatal DAergic innervation (Marin et al., 2013; Rommelfanger and Wichmann, 2010; Wilson and Bevan, 2011). Nigral DAergic neurons innervate the two segments of globus pallidus: the external part (GPe in primates or GP in rodents) and the internal part (GPi in primates or entopeduncular nucleus (EP) in rodents) (Fuchs and Hauber, 2004; Jan et al., 2000; Prensa et al., 2000; Smith and Villalba, 2008). The functions of both pallidal segments are distinguishable by differential distribution of DA receptor subtypes (Richfield et al., 1987; Rommelfanger and Wichmann, 2010), neuronal firing patterns and rates (DeLong et al., 1985; Sterio et al., 1994), and anatomical connections (Jaeger and Kita, 2011; Parent and Hazrati, 1995), suggesting different biological changes for both segments with PD progression (Cho et al., 2019).

In this line, it is worth to take in account that the pallidal DAergic afferents are considered as collateral of the nigrostriatal projections and specific nigro-pallidal projections (Bouali-Benazzouz et al., 2009; Rommelfanger and Wichmann, 2010; Smith and Kieval, 2000). Indeed, it has been suggested that DA fibers innervating the GPi are separate from both, the nigrostriatal fibers and those innervating the GPe (Cho et al., 2019; Rajput et al., 2008), and that may degenerate independently (Cho et al., 2019). Consequently, DA depletion in these structures might play a role in PD pathophysiology and in motor complications induced by antiparkinsonian therapies (Bouali-Benazzouz et al., 2009; Hauber and Lutz, 1999).

The gold-standard therapy for PD is the restoration of DA levels through the administration of the DA precursor L-Dopa, however, its use is limited by the development of disabling dyskinetic movements (Espay et al., 2018; Fabbrini et al., 2007). The role of DA depletion in the extrastriatal basal ganglia (BG) nuclei on L-Dopa-induced dyskinesia (LID) pathophysiology is still unknown. Nevertheless, in view of the physiologic actions of DA on pallidal neuronal activity it has been suggested that the loss of GPe and GPi DA might differentially contribute to LID development.

The activity of pallidal neurons is also modulated by serotonergic projections from the dorsal raphe nucleus (Eid and Parent, 2016). It has been suggested that serotonergic neurons may contribute to LID via the aberrant release of striatal DA (Carlsson et al., 2007, Carlsson et al., 2009; Carta et al., 2007, Carta et al., 2008, Carta et al., 2010; Carta and Björklund, 2018; Lindgren et al., 2010; Sellnow et al., 2019). However, the role of pallidal serotonergic function in LID is still controversial since in a postmortem study no differences in GPe serotonin (SER) and serotonin transporter (SERT) levels between dyskinetic and non-dyskinetic patients have been shown (Rylander et al., 2010).

The present study aimed to investigate the role of DAergic pallidal depletion on the development of LID. We studied the effects of a GP or EP injection of 6-OHDA on dyskinesia, and pallidal SER and SERT expression changes, induced by L-Dopa in 6-OHDA-lesioned rats.

Section snippets

Animals

Male Sprague-Dawley rats weighing 220–240 g were housed on a 12 h light/dark cycle with free access to food and water. All animal experiments were carried out following European (2010/63/UE) and Spanish (RD 53/2013) regulations for the care and use of laboratory animals and approved by the local Government (Generalitat de Catalunya).

Experimental design and protocol of treatments

In order to investigate the effect of DAergic GP and EP denervation on levodopa-induced abnormal involuntary movements, sham or 6-OHDA lesion of the GP or EP and/or

Control of GP and EP injection cannula

Rats used in all experiments were selected on the basis of histological examination of the GP or EP injection cannula tract by means of Nissl staining (Fig. 1). Nissl staining showed that intra-GP or intra-EP injection of 6-OHDA did not induce anatomical lesions.

Degree of pallidal and EP dopaminergic denervation after GP and EP 6-OHDA-induced lesions

In GP dopaminergic denervated animals, a significant decrease in ipsilateral GP DAT-immunoreactivity was observed in the MFB-sham plus GP-lesion when compared with the MFB-sham plus GP-sham group (p < 0.05) (Fig. 2). Ipsilateral GP

Discussion

In contrast to the well-characterized actions of DA loss in the striatum, the consequences of DA depletion in the globus pallidum are unknown. Activation of extrastriatal DA receptors in the pallidal segments has effects on neuronal activities (Hadipour-Niktarash et al., 2012; Mamad et al., 2015; Wichmann, 2019), being possible that the loss of DA at these sites differentially contributes to the development of some aspects of parkinsonism, and to some of therapeutic and side effects of

Acknowledgments

This research was supported by grants from the Minist Ministerio de Ciencia e Innovación, Spain.(FIS 11(02167)).

Declaration of competing interest

Authors have not conflict of interest.

References (89)

  • F. Fulceri et al.

    Abnormal involuntary movements (AIMs) following pulsatile dopaminergic stimulation: severe deterioration and morphological correlates following the loss of locus coeruleus neurons

    Brain Res.

    (2007)
  • W. Hauber et al.

    Dopamine D1 or D2 receptor blockade in the globus pallidus produces akinesia in the rat

    Behav. Brain Res.

    (1999)
  • W. Hauber et al.

    The effects of globus pallidus lesions on dopamine-dependent motor behavior in rats

    Neuroscience

    (1998)
  • D. Jaeger et al.

    Functional connectivity and integrative properties of globus pallidus neurons

    Neuroscience

    (2011)
  • C. Marin et al.

    Subthalamic 6-OHDA-induced lesion attenuates levodopa-induced dyskinesias in the rat model of Parkinson’s disease

    Exp. Neurol.

    (2013)
  • C. Marin et al.

    Early L-dopa, but not pramipexole, restores basal ganglia activity in partially 6-OHDA-lesioned rats

    Neurobiol. Dis.

    (2014)
  • C. Marin et al.

    From unilateral to bilateral parkinsonism: effects of lateralization on dyskinesias and associated molecular mechanisms

    Neuropharmacology

    (2015)
  • C.Y. Ostock et al.

    Striatal norepinephrine efflux in L-Dopa-induced dyskinesia

    Neurochem. Int.

    (2018)
  • A. Parent et al.

    Functional anatomy of the basal ganglia. II. The place of subthalamic nucleus and external pallidum in basal ganglia circuitry

    Brain Res. Brain Res. Rev.

    (1995)
  • C. Pifl et al.

    Effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on the regional distribution of brain monoamines in the rhesus monkey

    Neuroscience

    (1991)
  • L. Prensa et al.

    Dopaminergic innervation of human basal ganglia

    J. Chem. Neuroanat.

    (2000)
  • E. Querejeta et al.

    Intrapallidal D2 dopamine receptors control globus palidus neuron activity in the rat

    Neurosci. Lett.

    (2001)
  • A. Quiroga-Varela et al.

    What basal ganglia changes underlie the parkinsonian state? The significance of neuronal oscillatory activity

    Neurobiol. Dis.

    (2013)
  • D.N. Ruskin et al.

    Cocaine or selective block of dopamine transporters influences multisecond oscillations in firing rate in the globus pallidus

    Neuropsychopharmacology

    (2001)
  • V. Sgambato-Faure et al.

    Glutamatergic mechanisms in the dyskinesias induced by pharmacological dopamine replacement and deep brain stimulation for the treatment of Parkinson’s disease

    Prog. Neurobiol.

    (2012)
  • R. Smith et al.

    The role of pallidal serotonergic function in Parkinson’s disease dyskinesias: a positron emission tomography study

    Neurobiol. Aging

    (2015)
  • E. Shin

    Noradrenaline neuron degeneration contributes to motor impairments and development of L-Dopa-induced dyskinesia in a rat model of Parkinson’s disease

    Exp. Neurol.

    (2014)
  • Y. Smith et al.

    Anatomy of the dopamine system in the basal ganglia

    Trends Neurosci.

    (2000)
  • C.J. Wilson et al.

    Intrinsic dynamics and synaptic inputs control the activity patterns of subthalamic nucleus neurons in health and in Parkinson’s disease

    Neuroscience

    (2011)
  • H. Yuan et al.

    Histological, behavioural and neurochemical evaluation of medial forebrain bundle and striatal 6-OHDA lesions as rat models of Parkinson’s disease

    J. Neurosci. Methods

    (2005)
  • K.K. Yung et al.

    Immunocytochemical localization of D1 and D2 DA receptors in the basal ganglia of the rat: light and electron microscopy

    Neuroscience

    (1995)
  • B.Y. Zeng et al.

    Morphological changes in serotoninergic neuritis in the striatum and globus pallidus in levodopa primed MPTP treated common marmosets with dyskinesia

    Neurobiol. Dis.

    (2010)
  • B. Ballanger et al.

    Imaging dopamine and serotonin systems on MPTP monkeys: a longitudinal PET investigation of compensatory mechanisms

    J. Neurosci.

    (2016)
  • E. Bezard et al.

    Pathophysiology of levodopa-induced dyskinesia: potential for new therapies

    Nature Rev.

    (2001)
  • T. Boraud et al.

    Dopamine agonist-induced dyskinesias are correlated to both firing pattern and frequency alteration of pallidal neurons in the MPTP-treated monkeys

    Brain

    (2001)
  • S. Boyce et al.

    Nigrosriatal damage is required for induction of dyskinesias by L-DOPA in squirrel monkeys

    Clin. Neuropharmacol.

    (1990)
  • T. Carlsson et al.

    Serotonin neuron transplants exacerbate L-DOPA-induced dyskinesias in a rat model of Parkinson’s disease

    J. Neurosci.

    (2007)
  • T. Carlsson et al.

    Impact of grafted serotonin and dopamine neurons on development of L-DOPA-induced dyskinesias in parkinsonian rats is determined by the extent of dopamine neuron degeneration

    Brain

    (2009)
  • M. Carta et al.

    The serotonergic system in L-DOPA-induced dyskinesia: pre-clinical evidence and clinical perspective

    J. Neural Transm.

    (2018)
  • M. Carta et al.

    Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats

    Brain

    (2007)
  • M. Carta et al.

    Role of serotonin neurons in the induction of levodopa-and graft-induced dyskinesias in Parkinson’s disease

    Mov. Disord.

    (2010)
  • A.R. Crossman

    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.

    (1990)
  • M.R. DeLong et al.

    Primate globus pallidus and subthalamic nucleus: functional organization

    J. Neurophysiol.

    (1985)
  • D.A. Di Monte et al.

    Relationship among nigrostriatal denervation, parkinsonism, and dyskinesias in the MPTP primate model

    Mov. Disord.

    (2000)
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