Elsevier

Neuroscience

Volume 91, Issue 2, June 1999, Pages 587-597
Neuroscience

Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal dopaminergic function: a combined in vivo electrophysiological and microdialysis study

https://doi.org/10.1016/S0306-4522(98)00655-1Get rights and content

Abstract

Electrophysiological techniques and in vivo microdialysis were used to investigate the relative contribution of central serotonin-2C/2B and serotonin-2A receptor subtypes in the control of mesolimbic and nigrostriatal dopaminergic function. Thus, extracellular single-unit recordings were performed from neurochemically identified dopamine neurons in the ventral tegmental area and the substantia nigra pars compacta, as well as simultaneous monitoring of accumbal and striatal basal dopamine release in anesthetized rats following the administration of serotonin-2C/2B (SB 206553), serotonin-2A (SR 46349B) or serotonin-2A/2B/2C (ritanserin) antagonists. Administration of SB 206553 (40–160 μg/kg, i.v.) caused a dose-dependent increase in the basal firing rate of ventral tegmental area and nigral dopamine neurons, reaching its maximum (45.2 and 28.5%, respectively) following 160 μg/kg. Moreover, burst activity was significantly enhanced by SB 206553 in the ventral tegmental area only. In contrast, injection of SR 46349B (40–160 μg/kg, i.v.), and ritanserin (40–160 μg/kg, i.v.) did not cause any significant change in the basal activity of these neurons. Basal dopamine release was significantly enhanced in both the nucleus accumbens (42%) and the striatum (33%) following the intraperitoneal administration of 5 mg/kg SB 206553. In contrast, SR 46349B (0.5 mg/kg, s.c.) and ritanserin (0.63 mg/kg, i.p.) failed to affect basal dopamine output in both regions.

Taken together, these data indicate that the central serotonergic system exerts a tonic inhibitory control of mesolimbic and nigrostriatal dopaminergic pathway activity and that the serotonin-2C/2B receptor subtypes are involved in this effect. Moreover, these findings might open new possibilities for the employment of serotonin-2C/2B receptor antagonists in the treatment of neuropsychiatric disorders related to a hypofunction of central dopaminergic neurons.

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.

References (66)

  • F Jenck et al.

    Evidence for a role of 5-HT1C receptors in the antiserotonergic properties of some antidepressant drugs

    Eur. J. Pharmac.

    (1993)
  • G.A Kennett et al.

    SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist

    Neuropharmacology

    (1997)
  • G Mengod et al.

    The distribution and cellular localization of the serotonin 1C receptor mRNA in the rodent brain examined by in situ hybridization histochemistry. Comparison with receptor binding distribution

    Neuroscience

    (1990)
  • H Moukhles et al.

    Quantitative and morphometric data indicate precise cellular interactions between serotonin and postsynaptic targets in rat substantia nigra

    Neuroscience

    (1997)
  • A Pazos et al.

    Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors

    Brain Res.

    (1985)
  • M Pompeiano et al.

    Distribution of serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT2A and 5-HT2C receptors

    Molec. Brain Res.

    (1994)
  • C.E Rick et al.

    Excitation of rat substantia nigra pars reticulata neurons by 5-hydroxytryptamine in vitro: evidence for a direct action mediated by 5-hydroxytryptamine2C receptors

    Neuroscience

    (1995)
  • C.J Schmidt et al.

    5-HT2 receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4-methylenedioxymethamphetamine

    Eur. J. Pharmac.

    (1992)
  • I Van Wijngaarden et al.

    The concept of selectivity in 5-HT receptor research

    Eur. J. Pharmac.

    (1990)
  • R.Y Wang

    Dopaminergic neurons in the rat ventral tegmental area. I. Identification and characterization

    Brain Res. Rev.

    (1981)
  • J.L Andersson et al.

    Ritanserin potentiates the stimulatory effects of raclopride on neuronal activity and dopamine release selectively in the mesolimbic dopaminergic system

    Naunyn-Schmiedeberg's Arch. Pharmac.

    (1995)
  • C.H Ashby et al.

    Differential effect of the 5-HT2C/2B receptor antagonist SB 200646 and the selective 5-HT2A antagonist MDL 100907 on midbrain dopamine (DA) neurons in rats: an electrophysiological study

    Soc. Neurosci. Abstr.

    (1996)
  • E.C Azmitia et al.

    An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat

    J. comp. Neurol.

    (1978)
  • A.J Bean et al.

    Extracellular dopamine and neurotensin in rat prefrontal cortex in vivo: effects of median forebrain bundle stimulation frequency, stimulation pattern, and dopamine autoreceptors

    J. Neurosci.

    (1991)
  • D.W Bonhaus et al.

    The pharmacology and distribution of human 5-hydroxytryptamine2B (5-HT2B) receptor gene products: comparison with 5-HT2A and 5-HT2C receptors

    Br. J. Pharmac.

    (1995)
  • B.S Bunney et al.

    Dopaminergic neurons: effects of antipsychotic drugs and amphetamine on single cell activity

    J. Pharmac. exp. Ther.

    (1973)
  • L Cervo et al.

    Repeated treatment with imipramine and amitriptyline reduced the immobility of rats in the forced swimming test by enhancing dopamine mechanisms in the nucleus accumbens

    J. Pharm. Pharmac.

    (1988)
  • L.L Devaud et al.

    Alterations in extracellular and tissue levels of biogenic amines in rat brain induced by the serotonin2 receptor antagonist, ritanserin

    J. Neurochem.

    (1992)
  • S.L Dewey et al.

    Serotonergic modulation of striatal dopamine measured with positron emission tomography (PET) and in vivo microdialysis

    J. Neurosci.

    (1995)
  • M.S Duxon et al.

    Expression of 5-HT2B receptor protein in the rat

    Br. J. Pharmac.

    (1995)
  • K Eberle-Wang et al.

    Pattern of expression of the serotonin2C receptor messenger RNA in the basal ganglia of adult rats

    J. comp. Neurol.

    (1997)
  • T.P Flanigan et al.

    Evidence for the expression of the 5-HT2B receptor mRNA in the rat brain

    Br. J. Pharmac.

    (1995)
  • R.A Glennon

    Central serotonin receptors as targets for drug research

    J. med. Chem.

    (1987)
  • Cited by (0)

    View full text