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