Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal dopaminergic function: a combined in vivo electrophysiological and microdialysis study
Section snippets
Animals
Male Sprague–Dawley rats (Consorzio Mario Negri Sud, Italy and Iffa–Credo, Lyon, France), weighing 300–350 g, were used. Animals were kept at constant room temperature (21±2°C) and relative humidity (60%) with a 12-h light–dark cycle (dark from 8.00 p.m.), and had free access to water and food. Procedures involving animals and their care were conducted in conformity with the institutional guidelines that are in compliance with national (D.L. no. 116, G.U., Suppl. 40, 18 February 1992) and
Effects of SB 206553, SR 46349B and ritanserin on the basal activity of dopamine neurons in the ventral tegmental area
Administration of SB 206553 (40–160 μg/kg, i.v.; n=6 for each dose) caused a dose-dependent increase in the firing rate of VTA DA neurons (Fig. 1A). The effect was already evident at the dose of 40 μg/kg, which significantly enhanced the basal firing rate of dopaminergic cells by 17.6±11%. The maximum excitatory effect (45.2±15%) was observed after administration of 160 μg/kg; administration of higher doses of the drug did not cause further excitation of DA cell activity (not shown). A
Discussion
The results of this study confirm previous findings showing that the central 5-HT system elicits a tonic inhibitory control on mesolimbic and nigrostriatal DA activity, and provide the first evidence of the selective involvement of 5-HT2C/2B receptors in this effect. Previous electrophysiological studies suggested that 5-HT might exert a tonic inhibitory influence on VTA DA function by acting through 5-HT2C receptors.50 This conclusion was mainly based on the evidence that mesulergine, a 5-HT
Conclusions
This study provides evidence that the central 5-HT system, through the stimulation of 5-HT2C/2B receptors, exerts a tonic inhibitory control on both mesolimbic and nigrostriatal dopaminergic function. However, selective blockade of 5-HT2A receptors does not cause any significant change in basal dopaminergic function. These data might have implications for the possible use of 5-HT2C/2B antagonists in the treatment of neuropsychiatric disorders related to a hypofunction of central DA neurons.
Acknowledgements
This work was supported by the Italian National Research Council (Convenzione C.N.R.—Consorzio Mario Negri Sud), the CNR Short-term Mobility Program (year 1995) and grants from Bordeaux 2 University. We thank the Institut Féderatif de Recherche en Neuroscience Cliniques et Expérimentales (I.F.R.-I.N.S.E.R.M.-8 and F.R. C.N.R.S.-13, France) for financial support.
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