title: Activation of 5-HT6 receptors inhibits corticostriatal glutamatergic transmission.
abstract: We investigated the effect of 5-HT6 receptor subtype activation on glutamatergic transmission by means of whole-cell patch-clamp electrophysiological recordings from medium spiny neurons of the striatum and layer V pyramidal neurons of the prefrontal cortex. To this aim, we took advantage of a novel ligand, ST1936, showing nM affinity and agonist activity at the 5-HT6 receptor subtype. Our data show that 5-HT6 receptor activation by ST1936 reduces the frequency of spontaneous excitatory postsynaptic currents, with an IC50 of 1.3 μM. Moreover, 5-HT6 receptor activation also reduced the amplitude of spontaneous excitatory postsynaptic currents recorded from medium spiny neurons, suggesting a mechanism of action involving postsynaptic 5-HT6 receptors, as further confirmed by the paired-pulse analysis on evoked excitatory postsynaptic currents and by recordings of miniature glutamatergic events. The inhibitory effect of ST1936 on glutamatergic transmission was prevented by the selective 5-HT6 receptor antagonist SB258585 and mimicked by a different agonist, WAY-181187. Conversely, in the cortex ST1936 reduced the frequency, but not the amplitude, of spontaneous excitatory postsynaptic currents suggesting a presynaptic or indirect effect of the 5-HT6 receptor.
authors.affiliation: Laboratory of Neurophysiology and Plasticity, Fondazione Santa Lucia IRCCS, Roma, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Tassone
authors.forename: Graziella
authors.initials: G
authors.lastname: Madeo
authors.forename: Tommaso
authors.initials: T
authors.lastname: Schirinzi
authors.forename: Daniela
authors.initials: D
authors.lastname: Vita
authors.forename: Francesca
authors.initials: F
authors.lastname: Puglisi
authors.forename: Giulia
authors.initials: G
authors.lastname: Ponterio
authors.forename: Franco
authors.initials: F
authors.lastname: Borsini
authors.forename: Antonio
authors.initials: A
authors.lastname: Pisani
authors.forename: Paola
authors.initials: P
authors.lastname: Bonsi
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D005021:Ethylamines / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism* / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: C558115:2-(5-chloro-2-methyl-1H-indol-3-yl)-N,N-dimethylethanamine; D005021:Ethylamines; D007211:Indoles; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C097216:serotonin 6 receptor; D018698:Glutamic Acid