Preferential modulation of the GABAergic vs. dopaminergic function in the substantia nigra by 5-HT2C receptor

Abstract

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.