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