Elsevier

Neuroscience

Volume 202, 27 January 2012, Pages 424-433
Neuroscience

Neurodegeneration, Neuroprotection, and Disease-Oriented Neuroscience
Research Paper
Effects of noradrenaline and serotonin depletions on the neuronal activity of globus pallidus and substantia nigra pars reticulata in experimental parkinsonism

https://doi.org/10.1016/j.neuroscience.2011.11.024Get rights and content

Abstract

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.

Highlights

▶5-HT depletion induces dramatic changes in the firing activity of GP and SNr neurons. ▶Noradrenaline or 5-HT depletion did not potentiate the changes induced by DA depletion. ▶Noradrenaline and 5-HT depletion contribute to the dysregulation of the basal ganglia.

Section snippets

Animals

Adult male Sprague–Dawley rats, weighing 280–380 g were used. They were housed five per cage under artificial conditions of light (light/dark cycle, light on at 7:00 am), temperature (24 °C), and humidity (45%) with food and water available ad libitum. All animal experiments were carried out in accordance with European Communities Council Directive 2010/63/UE, and all efforts were made to minimize the number of animals used and their suffering.

Drugs

6-OHDA, DSP-4, pCPA, ascorbic acid, desipramine

Effect of 6-OHDA, DSP-4, and pCPA on monoamine tissue concentrations in the rat brain

Table 1 summarizes the tissue concentration values of DA in the anterior striatum and NA and 5-HT in the frontal cortex in the six experimental groups (see Fig. 1). The 6-OHDA, DSP-4, and pCPA administrations applied alone or combined (6-OHDA/DSP-4 and 6-OHDA/pCPA) induced a selective depletion of endogenous DA, NA, and 5-HT, respectively, without modifying other monoamines.

Discussion

The present study shows that additional depletion of NA or 5-HT to dopamine depletion influences in a region-dependent manner the electrophysiological properties of GP and SNr neurons. Although NA depletion alone did not alter GP and SNr neuronal activity, it dampened the pathological increase in irregular and bursty pallidal neurons induced by the DA depletion. 5-HT depletion alone induced similar effects to the 6-OHDA lesion (except for a decreased firing rate in the GP). The increased bursty

Conclusion

The results of the present study provide evidence that the 5-HT system plays a major role in the modulation of both the firing rate and patterns of GP and SNr neurons. Although the influence of the NA system on these brain regions is weak, it strongly modulates the activity of STN neurons (Delaville et al., in press). These data show that, in addition to the prominent influence of DA neurons on basal ganglia activity, NA and 5-HT neurons also participate in the overall homeostasis of this

Acknowledgments

Claire Delaville was supported by a fellowship from the “Ministère de l'Education Nationale, de la Recherche et de la Technologie” (MENRT). The University Bordeaux Segalen and the “Centre National de la Recherche Scientifique” (CNRS) funded this study. We wish to thank Dr. Martin Guthrie for english reading of the manuscript.

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