Preferential Modulation of the GABAergic vs. Dopaminergic Function in the Substantia Nigra by 5-HT2C Receptor

  • Giuseppe Di Giovanni
  • Vincenzo Di Matteo
  • Massimo Pierucci
  • Ennio Esposito
Conference paper
Part of the Advances in Behavioral Biology book series (ABBI, volume 58)


Serotonin (5-HT) is intimately involved in the modulation of the basal ganglia circuitry and in its pathologies. The 5-HT pivotal role is supported by anatomical evidence demonstrating a large serotonergic innervation throughout the basal ganglia, with the highest concentration of this indole in the substantia nigra (SN). Among all the 5-HT receptors present in the SN, the 5-HT2C receptor subtype seems to be one of the principal receptors through which 5-HT exerts its function. In this chapter, we present in vivo electrophysiology and microdialysis evidence showing that the selective activation of 5-HT2C receptors does not affect dopaminergic function whereas it has a profound impact on GABAergic function in the substantia nigra pars reticulata (SNr). 5-HT excites the neurons of the SNr by acting on 5-HT2C receptors, and this control seems to be phasic rather than tonic in nature. Consequently, activation of 5-HT2C receptors boosts the concentration of GABA in the SNr, likely increasing GABA somatodendritic release from SNr neurons and from other GABA-containing neurons projecting to the SNr as well. Therefore, drugs acting on 5-HT2C receptors may provide a novel non-dopaminergic target for improving therapies for some basal ganglia disorders such as Parkinson’s disease.


Gaba Release Extracellular Gaba Basal Ganglion Circuitry Basal Firing Rate Extracellular Gaba Level 



This work was supported in part by Ateneo di Palermo research funding, project ORPA068JJ5 (coordinator G. Di Giovanni).


  1. Alex KD, Yavanian GJ, McFarlane HG, Pluto CP and Pehek EA (2005) Modulation of dopamine release by striatal 5-HT2C receptors. Synapse 55: 242–251.CrossRefPubMedGoogle Scholar
  2. Basura GJ and Walker PD (1999) Serotonin 2A receptor mRNA levels in the neonatal dopamine-depleted rat striatum remain upregulated following suppression of serotonin hyperinnervation. Brain Res Dev Brain Res 116: 111–117.CrossRefPubMedGoogle Scholar
  3. Birkmayer W and Riederer P (1986) Biological aspects of depression in Parkinson’s disease. Psychopathology 19: 58–61.CrossRefPubMedGoogle Scholar
  4. Blackburn TP (2004) Serotonergic agents and Parkinson’s disease. Drug Discov Today Ther Strateg 1:35–41.CrossRefGoogle Scholar
  5. Blackburn TP, Minabe Y, Middlemiss DN, Shirayama Y, Hashimoto K and Ashby Jr CR (2002) Effect of acute and chronic administration of the selective 5-HT2C receptor antagonist SB-243213 on midbrain dopamine neurons in the rat: an in vivo extracellular single cell study. Synapse 46: 129–139.CrossRefPubMedGoogle Scholar
  6. Chase TN (1974) Serotonergic-dopaminergic interactions and extrapyramidal function. Adv Biochem Psychopharmacol 11:377–385.PubMedGoogle Scholar
  7. Corvaja N, Doucet G and Bolam JP (1993) Ultrastructure and synaptic targets of the raphe-nigral projection in the rat. Neuroscience 55: 417–427.CrossRefPubMedGoogle Scholar
  8. Deniau JM and Chevalier G (1992) The lamellar organization of the rat substantia nigra pars reticulata: distribution of projection neurons. Neuroscience 46: 361–377.CrossRefPubMedGoogle Scholar
  9. Di Giovanni G, De Deurwaerdére P, Di Mascio M, Di Matteo V, Esposito E and Spampinato U (1999) Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal dopaminergic function: a combined in vivo electrophysiological and microdialysis study. Neuroscience 91: 587–597.CrossRefPubMedGoogle Scholar
  10. Di Giovanni G, Di Matteo V, Di Mascio M and Esposito E (2000) Preferential modulation of mesolimbic vs. nigrostriatal dopaminergic function by serotonin(2C/2B) receptor agonists: a combined in vivo electrophysiological and microdialysis study. Synapse 35: 53–61.CrossRefPubMedGoogle Scholar
  11. Di Giovanni G, Di Matteo V, La Grutta V and Esposito E (2001) m-Chlorophenylpiperazine excites non-dopaminergic neurons in the rat substantia nigra and ventral tegmental area by activating serotonin-2C receptors. Neuroscience 103: 111–116.CrossRefPubMedGoogle Scholar
  12. Di Giovanni G, Di Matteo V and Esposito E (2002) Serotonin/dopamine interaction-focus on 5-HT2C receptor, a new target of psychotropic drugs. Indian J Exp Biol 40: 1344–1352.PubMedGoogle Scholar
  13. Di Giovanni G, Di Matteo V, Pierucci, Benigno A and Esposito E (2006a) Serotonin involvement in the basal ganglia pathophysiology: could the 5-HT2C receptor be a new target for therapeutic strategies? Curr Med Chem 13: 3069–3081.CrossRefPubMedGoogle Scholar
  14. Di Giovanni G, Di Matteo V, Pierucci M, Benigno A and Esposito E (2006b) Central serotonin2C receptor: from physiology to pathology. Curr Top Med Chem 6: 1909–1925.CrossRefPubMedGoogle Scholar
  15. Di Matteo V, Di Giovanni G, Di Mascio M and Esposito E (1999) SB 242084, a selective serotonin2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system. Neuropharmacology 38: 1195–1205.CrossRefPubMedGoogle Scholar
  16. Di Matteo V, De Blasi A, Di Giulio C and Esposito E (2001) Role of 5-HT(2C) receptors in the control of central dopamine function. Trends Pharmacol Sci 22: 229–232.CrossRefPubMedGoogle Scholar
  17. Di Matteo V, Pierucci M, Esposito E, Crescimanno G, Benigno A and Di Giovanni G (2008) Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson’s disease and other motor disorders. Prog Brain Res 172: 423–463.CrossRefPubMedGoogle Scholar
  18. Eberle-Wang K, Mikeladze Z, Uryu K and Chesselet MF (1997) Pattern of expression of the serotonin2C receptor messenger RNA in the basal ganglia of adult rats. J Comp Neurol 384: 233–247.CrossRefPubMedGoogle Scholar
  19. Fibiger HC and Miller JJ (1977) An anatomical and electrophysiological investigation of the serotonergic projection from the dorsal raphe nucleus to the substantia nigra in the rat. Neuroscience 2: 975–987.CrossRefGoogle Scholar
  20. Fox SH and Brotchie JM (2000a) 5-HT(2C) receptor antagonists enhance the behavioural response to dopamine D(1) receptor agonists in the 6-hydroxydopamine-lesioned rat. Eur J Pharmacol 398: 59–64.CrossRefPubMedGoogle Scholar
  21. Fox SH and Brotchie JM (2000b) 5-HT2C receptor binding is increased in the substantia nigra pars reticulata in Parkinson’s disease. Mov Disord 15: 1064–1069.CrossRefPubMedGoogle Scholar
  22. Fox SH, Moser B and Brotchie JM (1998) Behavioral effects of 5-HT2C receptor antagonism in the substantia nigra zona reticulata of the 6-hydroxydopamine-lesioned rat model of Parkinson’s disease. Exp Neurol 151: 35–49.CrossRefPubMedGoogle Scholar
  23. Hoffman BJ and Mezey E (1989) Distribution of serotonin 5-HT1C receptor mRNA in adult rat brain. FEBS Lett 247: 453–462.CrossRefPubMedGoogle Scholar
  24. Hoyer D, Hannon JP and Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71: 533–554.CrossRefPubMedGoogle Scholar
  25. Invernizzi RW, Pierucci M, Calcagno E, Di Giovanni G, Di Matteo V, Benigno A and Esposito E (2007) Selective activation of 5-HT(2C) receptors stimulates GABA-ergic function in the rat substantia nigra pars reticulata: a combined in vivo electrophysiological and neurochemical study. Neuroscience 144: 1523–1535.CrossRefPubMedGoogle Scholar
  26. Marquis KL, Sabb AL, Logue SF, Brennan JA, Piesla MJ, Comery TA, Grauer SM, Ashby CR Jr, Nguyen HQ, Dawson LA, Barrett JE, Stack G, Meltzer HY, Harrison BL and Rosenzweig-Lipson S (2007) WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole]: a novel 5-hydroxytryptamine 2C receptor-selective agonist with preclinical antipsychotic-like activity. J Pharmacol Exp Ther 320: 486–496.CrossRefPubMedGoogle Scholar
  27. Mengod G, Nguyen H, Le H, Waeber C, Lübbert H and Palacios JM (1990) 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 35: 577–591.CrossRefPubMedGoogle Scholar
  28. Mori S, Matsuura T, Takino T and Sano Y (1987) Light and electron microscopic immunohistochemical studies of serotonin nerve fibers in the substantia nigra of the rat, cat and monkey. Anat Embryol 176: 13–18.CrossRefPubMedGoogle Scholar
  29. Moukhles H, Bosler O, Bolam JP, Vallée A, Umbriaco D, Geffard M and Doucet G (1997) Quantitative and morphometric data indicate precise cellular interactions between serotonin and postsynaptic targets in rat substantia nigra. Neuroscience 76: 1159–1171.CrossRefPubMedGoogle Scholar
  30. Nicholson SL and Brotchie JM (2002) 5-Hydroxytryptamine (5-HT, serotonin) and Parkinson’s disease – opportunities for novel therapeutics to reduce the problems of levodopa therapy. Eur J Neurol 9: 1–6.CrossRefPubMedGoogle Scholar
  31. Numan S, Lundgren KH, Wright DE, Herman JP and Seroogy KB (1995) Increased expression of 5HT2 receptor mRNA in rat striatum following 6-OHDA lesions of the adult nigrostriatal pathway. Brain Res Mol Brain Res 29: 391–396.CrossRefPubMedGoogle Scholar
  32. Pasqualetti M, Ori M, Castagna M, Marazziti D, Marazziti D, Cassano GB and Nardi I (1999) Distribution and cellular localization of the serotonin type 2C receptor messenger RNA in human brain. Neuroscience 92: 601–611.CrossRefPubMedGoogle Scholar
  33. Rick CE, Stamford IM and Lacey MG (1995) Excitation of rat substantia nigra pars reticulata neurons by 5-hydroxytryptamine in vitro: evidence for a direct action mediated by 5-hydroxytryptamine2C receptors. Neuroscience 69: 903–913.CrossRefPubMedGoogle Scholar
  34. Soubrié P, Reisine TD and Glowinski J (1984) Functional aspects of serotonin transmission in the basal ganglia: a review and an in vivo approach using the push-pull cannula technique. Neuroscience 13: 605–625.CrossRefPubMedGoogle Scholar
  35. Stanford IM and Lacey MG (1996) Differential actions of serotonin, mediated by 5-HT1B and 5-HT2C receptors, on GABA-mediated synaptic input to rat substantia nigra pars reticulata neurons in vitro. J Neurosci 16: 7566–7573.PubMedGoogle Scholar
  36. Ward RP and Dorsa DM (1996) Colocalization of serotonin receptor subtypes 5-HT2A, 5-HT2C, and 5-HT6 with neuropeptides in rat striatum. J Comp Neurol 370: 405–414.CrossRefPubMedGoogle Scholar
  37. Zhang X, Andren PE and Svenningsson P (2007) Changes on 5-HT2 receptor mRNAs in striatum and subthalamic nucleus in Parkinson’s disease model. Physiol Behav 92: 29–33.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Giuseppe Di Giovanni
    • 1
  • Vincenzo Di Matteo
    • 2
  • Massimo Pierucci
    • 2
  • Ennio Esposito
    • 2
  1. 1.Dipartimento di Medicina Sperimentale, Sezione di Fisiologia Umana, “G. Pagano,”Università degli Studi di PalermoPalermoItaly
  2. 2.Istituto di Ricerche Farmacologiche “Mario Negri”Consorzio Mario Negri SudSanta Maria Imbaro (CH)Italy

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