Intrapallidal administration of 6-hydroxydopamine mimics in large part the electrophysiological and behavioral consequences of major dopamine depletion in the rat
Introduction
Parkinson’s disease (PD) is a neurological disorder characterized by the progressive degeneration of dopamine neurons in the pars compacta of the substantia nigra (SNc), resulting in a loss of dopamine in the striatum (Ehringer and Hornykiewicz, 1960). This discovery contributed to the development of dopamine replacement therapy in PD (Andén et al., 1970) and the understanding of the mechanisms by which dopamine modulates neuronal function in the striatum (for review, Nicola et al., 2000). Another contribution was the concept of the “direct and indirect” pathways model of basal ganglia circuitry (Albin et al., 1989, Alexander and Crutcher, 1990, Bergman et al., 1990), which was at the origin of the development of a new neurosurgical therapy of PD by subthalamic nucleus (STN) high-frequency stimulation (Benazzouz et al., 1993, Limousin et al., 1995). This basic model represented an oversimplification of the basal ganglia organization and many studies have led to its refinement for better understanding of how dopamine regulates the basal ganglia and how it contributes to the pathophysiology of PD (for review, Smith and Villalba, 2008).
While the striatum is by far the main target of SNc dopamine neurons, dopamine can mediate its regulatory function at various levels of the basal ganglia circuitry, including the globus pallidus (GP) and STN (Smith and Kieval, 2000, Smith and Villalba, 2008).
The GP and STN are two interconnected nuclei of the indirect pathway (Parent and Hazrati, 1995a). Although GP and STN neurons pattern each other’s activity, the GP is considered as a structure controlling the electrical activity of STN neurons by means of its GABAergic projections (Hallworth and Bevan, 2005, Baufreton et al., 2009). In addition to massive GABAergic axon terminals from the striatum and glutamatergic afferents from the STN and the parafascicular nucleus of the thalamus (Kincaid et al., 1991, Mouroux et al., 1997), GP receives dopaminergic afferents from the SNc. These dopaminergic afferents are considered as collaterals of the nigrostriatal projections (François et al., 1999, Smith and Kieval, 2000, Bouali-Benazzouz et al., 2009) and specific nigro-pallidal projections (Jan et al., 2000, Smith and Kieval, 2000, Rommelfanger and Wichmann, 2010). Recent evidence suggests that dopamine modulates GP function and that dopamine receptor blockade or dopamine depletion at this site contributes to motor deficits (Hauber and Lutz, 1999, Bouali-Benazzouz et al., 2009).
Dopamine in the GP controls both GABAergic and glutamatergic inputs via D1 and D2 receptor subtypes (Floran et al., 1990, Floran et al., 1997, Cooper and Stanford, 2001, Shin et al., 2003, Hernández et al., 2006). In turn, GP neurons send inhibitory GABAergic projections to the STN and the substantia nigra pars reticulata (SNr) (Parent and Hazrati, 1995b, Rommelfanger and Wichmann, 2010). Nevertheless, the impact of dopamine depletion in GP on the modulation of these pallido-subthalamic and pallido-nigral projections is not known.
The present study aimed to investigate the effects of intrapallidal injection of 6-hydroxydopamine (6-OHDA), on the electrical activity of STN and SNr neurons using in vivo extracellular single-unit recordings in the rat and on motor behavior, using the “open field” actimeter and the stepping test.
Section snippets
Animals
Adult male Sprague–Dawley rats, weighing 280–360 g, were used in this study. Animals were housed three per cage, kept under artificial conditions of light (12-h light/dark cycle, light on at 7:00 A.M.), temperature (24 °C), and humidity (45%) with food and water available ad libitum. All efforts were made to minimize the number of animals used and their suffering. Experiments were carried out in accordance with the European Communities Council Directive (EU Directive 2010/63/EU) and the National
6-OHDA injection into GP reduced dopamine tissue content in the GP and striatum
Results of biochemical analysis are summarized in Table 1. As expected, 6-OHDA injection into GP significantly decreased the tissue content of DA in the GP of 6-OHDA-lesioned side compared to the intact side (−90%, p < 0.001) and to the same side of sham rats (−86%, p < 0.01). In addition, 6-OHDA injection into GP significantly reduced the tissue content of DA in the dorsal striatum (by 85%, p < 0.001 in comparison with the intact side of 6-OHDA rats and by 79%, p < 0.01 in comparison with the same
Discussion
Our results show for the first time that intrapallidal injection of 6-OHDA resulted in a dramatic depletion of DA within the GP and the striatum resulting in motor deficits paralleled by changes in the firing activity of STN and SNr neurons.
Conclusion
Our data provide evidence that intrapallidal injection of 6-OHDA resulted in motor deficits paralleled by changes in the firing activity of STN and SNr neurons, which mimic in large part those obtained after major dopamine depletion in the classical rat model of PD. Our data suggest that the observed changes are the consequence of a combined depletion of dopamine in the GP and in the striatum. Moreover, they support the assumption that in addition to its action in the striatum, dopamine
Conflicts of interest
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 three years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. This article has not been submitted elsewhere. All co-authors have seen and agree with the contents of the manuscript.
Acknowledgments
This study was supported by the “Centre National de la Recherche Scientifique (CNRS)”, the “Université Bordeaux Segalen” and exchange grants of the GDRI N198 (CNRS & INSERM France, and CNRST Morocco), Egide-Volubilis No. 20565ZM, CNRS-CNRST Convention Adivmar 22614 and NEUROMED.
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