Effects of noradrenaline and serotonin depletions on the neuronal activity of globus pallidus and substantia nigra pars reticulata in experimental parkinsonism

Université Bordeaux Segalen, Centre National de la Recherche Scientifique (CNRS UMR 5293), Neurodegenerative Diseases Institute, 146 rue Léo-Saignat, 33076 Bordeaux Cedex, France.
Neuroscience (Impact Factor: 3.36). 11/2011; 202:424-33. DOI: 10.1016/j.neuroscience.2011.11.024
Source: PubMed


Parkinson's disease (PD) is characterized by a degeneration of dopaminergic neurons and also by a degradation of noradrenergic neurons from the locus coeruleus and serotonergic neurons from the dorsal raphe. However, the effect of these depletions on the neuronal activity of basal ganglia nuclei is still unknown. By using extracellular single-unit recordings, we have addressed this question by testing the effects of selective depletions of noradrenaline (NA) (with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4)) and serotonin (5-HT) (with 4-chloro-l-phenylalanine (pCPA)) on the neuronal activity of globus pallidus (GP) and substantia nigra pars reticulata (SNr) neurons in the 6-hydroxydopamine (6-OHDA) rat model of PD and sham-lesioned rats. We showed that 6-OHDA-induced dopamine (DA) depletion resulted in an increased number of GP and SNr neurons discharging in a bursty and irregular manner, confirming previous studies. These pattern changes were region-dependently influenced by additional monoamine depletion. Although the number of irregular and bursty neurons in 6-OHDA rats tended to decrease in the GP after NA depletion, it did not change after pCPA treatment in both GP and SNr. Furthermore, a significant interaction between DA and 5-HT depletions was observed on the firing rate of SNr neurons. By themselves, NA depletion did not change GP or SNr neuronal activity, whereas 5-HT depletion decreased the firing rate and increased the proportion of bursty and irregular neurons in both brain regions, suggesting that 5-HT, but not NA, plays a major role in the modulation of both the firing rate and patterns of GP and SNr neurons. Finally, our data suggest that, in addition to the primary role of DA in the control of basal ganglia activity, NA and 5-HT depletion also contribute to the dysregulation of the basal ganglia in PD by changes to neuronal firing patterns.


Available from: Claire Delaville
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    • "Globus pallidus (GP) and substantia nigra (SN), for example, receive fewer noradrenergic afferents than STN (Pifl et al., 1991). Moreover, noradrenergic depletion did not appear to significantly alter the firing patterns within GP and SN in 6-hydroxydopamine lesioned rats (Delaville et al., 2012a). It might be the case, then, that dexmedetomidine-induced sedation is more suitable for DBS indications such as dystonia. "
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    ABSTRACT: Dexmedetomidine (an alpha-2 adrenergic agonist) sedation is commonly used during subthalamic nucleus (STN) deep brain stimulation (DBS). Its effects on the electrophysiological characteristics of human STN neurons are largely unknown. We hypothesized that dexmedetomidine modulates the firing rates and bursting of human STN neurons. We analyzed microelectrode recording (MER) data from patients with Parkinson's disease who underwent STN DBS. A 'Dex bolus' group (dexmedetomidine bolus prior to MER, 27 cells from 7 patients) was compared with a 'no sedation' group (29 cells from 11 patients). We also performed within-patient comparisons with varying dexmedetomidine states. Cells were classified as dorsal half or ventral half based on their relative location in the STN. Neuronal burst and oscillation characteristics were analyzed using the Kaneoke-Vitek methodology and local field potential (LFP) oscillatory activity was also interrogated. Dexmedetomidine was associated with a slight increase in firing rate (41.1±9.9 Hz vs. 34.5±10.6 Hz, p = .02) but a significant decrease in burstiness (number of bursts, p = .02; burst index, p < .001; percentage of spike in burst, p = .002) of dorsal but not ventral STN neurons. No associated differences in beta spike oscillations (spike oscillation beta peak, p = .4; signal-to-noise ratio in the beta range for spikes and bursts, p = .3 and p = .5, respectively) and LFP beta power (p = .17) were observed. Since bursting pattern is often used to help identify STN and guide electrode placement, we recommend that high-dose dexmedetomidine should be avoided during DBS surgery. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Neuroscience 06/2015; 42(4). DOI:10.1111/ejn.13004 · 3.18 Impact Factor
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    • "The globus pallidus (GP) has two segments, the external GP (GPe), which has a central position in the BG loop, and the internal GP (GPi/EP), which, together with the SNr, form the output structures of the BG. In the GPe, 5-HT depletion decreases the firing frequency and increases the proportion of bursty and irregular neurons (Delaville et al., 2012b). In contrast, local application of 5-HT or selective serotonin reuptake inhibitor (SSRI) administration excites most of GPe neurons (Querejeta et al., 2005; Zhang et al., 2010; Wang et al., 2013). "
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    ABSTRACT: The neurotransmitter serotonin (5-HT) has a multifaceted function in the modulation of information processing through the activation of multiple receptor families, including G-protein-coupled receptor subtypes (5-HT1, 5-HT2, 5-HT4-7) and ligand-gated ion channels (5-HT3). The largest population of serotonergic neurons is located in the midbrain, specifically in the raphe nuclei. Although the medial and dorsal raphe nucleus (DRN) share common projecting areas, in the basal ganglia (BG) nuclei serotonergic innervations come mainly from the DRN. The BG are a highly organized network of subcortical nuclei composed of the striatum (caudate and putamen), subthalamic nucleus (STN), internal and external globus pallidus (or entopeduncular nucleus in rodents, GPi/EP and GPe) and substantia nigra (pars compacta, SNc, and pars reticulata, SNr). The BG are part of the cortico-BG-thalamic circuits, which play a role in many functions like motor control, emotion, and cognition and are critically involved in diseases such as Parkinson's disease (PD). This review provides an overview of serotonergic modulation of the BG at the functional level and a discussion of how this interaction may be relevant to treating PD and the motor complications induced by chronic treatment with L-DOPA.
    Frontiers in Neural Circuits 03/2014; 8:21. DOI:10.3389/fncir.2014.00021 · 3.60 Impact Factor
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    • "Yes [62] Yes [63] Yes [64] Yes [65] Yes [66] Ast [66], Mic [66], Oligo [66] Parkinson's disease Yes [67] Yes [68] Yes [69] Yes [70] Yes [65] Yes [71] Ast [72], Mic [72], Oligo [72] Amyotrophic lateral sclerosis Yes [32] Yes [58] Yes [5] Yes [73] Yes [74] Yes [75] Ast [75], Mic [75], Oligo [76] Multiple sclerosis Yes [2] Yes [2] Yes [77] Yes [78] Yes [79] Yes [80] Ast [81], Mic [82], Oligo [80] Major depression Yes [3] Yes [83] Yes [84] Yes [85] Yes [86] Yes [87] Ast [88], Mic [89], Oligo [90] Bipolar disorder Yes [3] Yes [91] Yes [92] Yes [93] Yes [94] Yes [95] Ast [95], Mic [95], Oligo [96] "
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    ABSTRACT: Damage to the locus ceruleus, with a subsequent decrease of CNS noradrenaline, occurs in a wide range of neurodegenerative, demyelinating and psychiatric disorders. The cause of the initial locus ceruleus damage remains unknown. Recently, inorganic mercury was found to enter human locus ceruleus neurons selectively. This has led to the formulation of a new hypothesis as to the cause of these disorders. Toxicants enter locus ceruleus neurons selectively, aided by the extensive exposure these neurons have to CNS capillaries, as well as by stressors that upregulate locus ceruleus activity. The resulting noradrenaline dysfunction affects a wide range of CNS cells and can trigger a number of neurodegenerative (Alzheimer's, Parkinson's and motor neuron disease), demyelinating (multiple sclerosis), and psychiatric (major depression and bipolar disorder) conditions. This hypothesis proposes that environmental toxicants entering the locus ceruleus can give rise to a variety of CNS disorders. Proposals are made for experiments to gain further evidence for this hypothesis. If it is shown that toxicants in the locus ceruleus are responsible for these conditions, attempts can be made to prevent the toxicant exposures or to remove the toxicants from the nervous system.
    Medical Hypotheses 11/2013; 82(1). DOI:10.1016/j.mehy.2013.11.016 · 1.07 Impact Factor
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