Antagonism of 5-HT1A receptors uncovers an excitatory effect of SSRIs on 5-HT neuronal activity, an action probably mediated by 5-HT7 receptors

Fokko J. Bosker*, Joost H. A. Folgering, Anatoliy V. Gladkevich, Anne Schmidt, Marieke C. G. van der Hart, Jeffrey Sprouse, Johan A. den Boer, Ben H. C. Westerink, Thomas I. F. H. Cremers

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

28 Citations (Scopus)

Abstract

Both microdialysis and electrophysiology were used to investigate whether another serotonin (5-HT) receptor subtype next to the 5-HT1A autoreceptor is involved in the acute effects of a selective serotonin reuptake inhibitor on 5-HT neuronal activity. On the basis of a previous study, we decided to investigate the involvement of the 5-HT7 receptors. Experiments were performed with the specific 5-HT7 antagonist SB 258741 and the putative 5-HT7 agonist AS19. In this study WAY 100.635 was used to block 5-HT1A receptors. Systemic administration of SB 258741 significantly reduced the effect of combined selective serotonin reuptake inhibitor and WAY 100.635 administration on extracellular 5-HT in the ventral hippocampus as well as 5-HT neuronal firing in the dorsal raphe nucleus. In the microdialysis study, co-administration of AS19 and WAY 100.635 showed a biphasic effect on extracellular 5-HT in ventral hippocampus, hinting at opposed 5-HT7 receptor mediated effects. In the electrophysiological experiments, systemic administration of AS19 alone displayed a bell-shaped dose-effect curve: moderately increasing 5-HT neuronal firing at lower doses while decreasing it at higher doses. SB 258741 was capable of blocking the effect of AS19 at a low dose. This is consistent with the pharmacological profile of AS19, displaying high affinity for 5-HT7 receptors and moderate affinity for 5-HT1A receptors. The data are in support of an excitatory effect of selective serotonin reuptake inhibitors on 5-HT neuronal activity mediated by 5-HT7 receptors. It can be speculated, that the restoration of 5-HT neuronal firing upon chronic antidepressant treatment, which is generally attributed to desensitization of 5-HT1A receptors alone, in fact results from a shift in balance between 5-HT1A and 5-HT7 receptor function.

Original languageEnglish
Pages (from-to)1126-1135
Number of pages10
JournalJournal of Neurochemistry
Volume108
Issue number5
DOIs
Publication statusPublished - Mar-2009

Keywords

  • AS19
  • citalopram
  • hippocampus
  • raphe nucleus
  • SB 258741
  • WAY 100
  • 635
  • DORSAL RAPHE NUCLEUS
  • ADENYLYL-CYCLASE
  • EXTRACELLULAR 5-HYDROXYTRYPTAMINE
  • PHARMACOLOGICAL CHARACTERIZATION
  • ELECTROPHYSIOLOGICAL RESPONSES
  • SEROTONIN TRANSPORTER
  • RELEASE INVIVO
  • RAT-BRAIN
  • IN-VITRO
  • PIG

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