Elsevier

Neuroscience

Volume 169, Issue 1, 11 August 2010, Pages 158-170
Neuroscience

Cognitive, Behavioral, and Systems Neuroscience
Research Paper
Stimulation of serotonin2C receptors elicits abnormal oral movements by acting on pathways other than the sensorimotor one in the rat basal ganglia

https://doi.org/10.1016/j.neuroscience.2010.04.061Get rights and content

Abstract

Serotonin2C (5-HT2C) receptors act in the basal ganglia, a group of sub-cortical structures involved in motor behavior, where they are thought to modulate oral activity and participate in iatrogenic motor side-effects in Parkinson's disease and Schizophrenia. Whether abnormal movements initiated by 5-HT2C receptors are directly consequent to dysfunctions of the motor circuit is uncertain. In the present study, we combined behavioral, immunohistochemical and extracellular single-cell recordings approaches in rats to investigate the effect of the 5-HT2C agonist Ro-60-0175 respectively on orofacial dyskinesia, the expression of the marker of neuronal activity c-Fos in basal ganglia and the electrophysiological activity of substantia nigra pars reticulata (SNr) neuron connected to the orofacial motor cortex (OfMC) or the medial prefrontal cortex (mPFC). The results show that Ro-60-0175 (1 mg/kg) caused bouts of orofacial movements that were suppressed by the 5-HT2C antagonist SB-243213 (1 mg/kg). Ro-60-0175 (0.3, 1, 3 mg/kg) dose-dependently enhanced Fos expression in the striatum and the nucleus accumbens. At the highest dose, it enhanced Fos expression in the subthalamic nucleus, the SNr and the entopeduncular nucleus but not in the external globus pallidus. However, the effect of Ro-60-0175 was mainly associated with associative/limbic regions of basal ganglia whereas subregions of basal ganglia corresponding to sensorimotor territories were devoid of Fos labeling. Ro-60-0175 (1–3 mg/kg) did not affect the electrophysiological activity of SNr neurons connected to the OfMC nor their excitatory-inhibitory-excitatory responses to the OfMC electrical stimulation. Conversely, Ro-60-0175 (1 mg/kg) enhanced the late excitatory response of SNr neurons evoked by the mPFC electrical stimulation. These results suggest that oral dyskinesia induced by 5-HT2C agonists are not restricted to aberrant signalling in the orofacial motor circuit and demonstrate discrete modifications in associative territories.

Section snippets

Animals

Male Sprague–Dawley rats (Charles River, Lyon, France) weighing 330–380 g were used. Animals were kept at constant room temperature (21±2 °C) and relative humidity (60%) with a 12-light/dark cycle (dark from 8 pm) and had free access to water and food. All animal use procedures conformed to International European Ethical Standards (86/609-EEC) and the French National Committee (décret 87/848) for the care and use of laboratory animals. All efforts were made to minimize animal suffering and to

Oral movements induced by peripheral administration of Ro-60-0175: role of 5-HT2C receptors

I.p. injection of 1 mg/kg of Ro-60-0175 elicited a significant increase in oral bouts [P<0.001 after a significant one-way ANOVA; Fig. 1]. The incidence of oral bouts was maximal 40-min after the injection of the drug (Inset Fig. 1). The effect of Ro-60-0175 slowly decreased without reaching control values 1 h after its administration. Its effect has been studied in the presence of the 5-HT2C antagonist SB-243213 (1 mg/kg), administered i.p. 1-h before Ro-60-0175. SB-243213, without effect by

Discussion

The present study was undertaken to determine the extent to which the abnormal orofacial movements induced by 5-HT2C receptor stimulation affects the sensorimotor parts within basal ganglia. Our results provide evidence that 5-HT2C receptor stimulation induces orofacial dyskinesia independently from molecular or electrophysiological changes along the sensorimotor pathway. Rather, they suggest that 5-HT2C agonists act preferentially within the associative and limbic territories of basal ganglia.

Conclusion

In conclusion, this work is the first to demonstrate that abnormal orofacial movements elicited by a 5-HT2C receptor agonist is not directly related to changes of activity in the sensorimotor territories of basal ganglia, and would rather correspond to the involvement of the associative/limbic territories.

Acknowledgments

This work was supported by grants from Centre National de la Recherche Scientifique and Bordeaux 2 University. We are grateful to Dr. M. Wood (Psychiatry CEDD, GlaxoSmithKline, Harlow, UK) and Dr. P Weber (Hoffman-LaRoche, Bale, Switzerland) for the generous gift of SB-243213 and Ro-60-0175, respectively. The authors wish to thank Dr. M. Lucas and Dr. B. Ballion for technical support and Dr. Martin Guthrie for correcting English language.

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