title: Pharmacological Evidence for 5-HT6 Receptor Modulation of 5-HT Neuron Firing in Vivo.
abstract: 5-Hydroxytryptamine (5-HT) neurons in the midbrain dorsal raphe nucleus (DRN) are implicated in the drug treatment and pathophysiology of a wide variety of neuropsychiatric disorders. Accumulating evidence suggests that 5-HT6 receptors may be located and functional in the DRN; therefore, 5-HT6 receptor ligands may have potential as novel modulators of 5-HT neurotransmission. The current study investigated the effect of intravenous (i.v.) administration of the selective 5-HT6 receptor agonist, WAY-181187, and antagonist, SB-399885, on the firing of 5-HT neurons in the DRN in vivo. Extracellular recordings were made in the DRN of anesthetized rats, and single 5-HT neurons were identified on the basis of electrophysiological properties combined with juxtacellular labeling and postmortem immunohistochemical analysis. WAY-181187 (1-4 mg/kg i.v.) caused a dose-dependent increase in 5-HT neuron firing rate. In comparison, SB-399885 (0.125-1 mg/kg i.v.) caused a dose-dependent decrease in 5-HT neuron firing rate, an effect reversed by WAY-181187 (3 mg/kg i.v.). These effects of WAY-181187 and SB-399885 were observed in two separate sets of experiments. In summary, the current data show the modulation of 5-HT neuronal firing by the 5-HT6 ligands WAY-181187 and SB-399885 and are consistent with the presence of 5-HT6 receptor-mediated positive feedback control of 5-HT neurons.
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Julia T
authors.initials: JT
authors.lastname: Brouard
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Judith V
authors.initials: JV
authors.lastname: Schweimer
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Houlton
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Burnham
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Quérée
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Trevor
authors.initials: T
authors.lastname: Sharp
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology*; D000818:Animals; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D008839:Microelectrodes; D010879:Piperazines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D059326:Serotonergic Neurons / Q000187:drug effects* / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology; D014363:Tryptamines / Q000494:pharmacology
chemical_list: C525454:N(1)-(6-chloroimidazo(2,1-b)(1,3)thiazole-5-sulfonyl)tryptamine; D010879:Piperazines; D011985:Receptors, Serotonin; C503990:SB 399885; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D013844:Thiazoles; D014363:Tryptamines; C097216:serotonin 6 receptor
keywords: 5-HT; 5-HT6 receptor; 5-Hydroxytryptamine; dorsal raphe nucleus; electrophysiology; serotonin