Abstract
During recent years, much attention has been devoted at investigating the modulatory role of central 5-HT2C receptors on dopamine (DA) neuron activity, and it has been proposed that these receptors modulate selectively DA exocytosis associated with increased firing of DA neurons. In the present study, using in vivo microdialysis in the nucleus accumbens (NAc) and the striatum of halothane-anesthetized rats, we addressed this hypothesis by assessing the ability of 5-HT2C agents to modulate the increase in DA outflow induced by haloperidol and cocaine, of which the effects on DA outflow are associated or not with an increase in DA neuron firing, respectively. The intraperitoneal administration of cocaine (10–30 mg/kg) induced a dose-dependent increase in DA extracellular levels in the NAc and the striatum. The effect of 15 mg/kg cocaine was potentiated by the mixed 5-HT2C/2B antagonist SB 206553 (5 mg/kg i.p.) and the selective 5-HT2C antagonist SB 242084 (1 mg/kg i.p.) in both brain regions. The mixed 5-HT2C/2B agonist, Ro 60-0175 (1 mg/kg i.p.), failed to affect cocaine-induced DA outflow, but reduced significantly the increase in DA outflow induced by the subcutaneous administration of 0.1 mg/kg haloperidol. The obtained results provide evidence that 5-HT2C receptors exert similar effects in both the NAc and the striatum, and they modulate DA exocytosis also when its increase occurs independently from an increase in DA neuron impulse activity. Furthermore, they show that 5-HT2C agonists, at variance with 5-HT2C antagonists, exert a preferential control on the impulse-stimulated release of DA.
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Acknowledgements
This work was supported by grants from Centre National de la Recherche Scientifique and Bordeaux 2 University. S Navailles was a fellowship recipient from the Ministère de la Recherche et de l'Enseignement Supérieur during the course of this study. We are grateful to Dr M Wood (Psychiatry CEDD, GlaxoSmithKline, Harlow, UK) for the generous gift of SB 206553 and SB 242084 and Dr P Weber (F Hoffmann-La Roche, Basel, Switzerland) for the gift of Ro 60-0175. We thank D Moison for the technical assistance.
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Navailles, S., De Deurwaerdère, P., Porras, G. et al. In Vivo Evidence that 5-HT2C Receptor Antagonist but not Agonist Modulates Cocaine-Induced Dopamine Outflow in the Rat Nucleus Accumbens and Striatum. Neuropsychopharmacol 29, 319–326 (2004). https://doi.org/10.1038/sj.npp.1300329
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DOI: https://doi.org/10.1038/sj.npp.1300329
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