Antagonism of 5-HT(1A) receptors uncovers an excitatory effect of SSRIs on 5-HT neuronal activity, an action probably mediated by 5-HT(7) receptors

• Published in: Journal of neurochemistry Vol. 108; no. 5; p. 1126
• Main Authors: Bosker, Fokko J, Folgering, Joost H A, Gladkevich, Anatoliy V, Schmidt, Anne, van der Hart, Marieke C G, Sprouse, Jeffrey, den Boer, Johan A, Westerink, Ben H C, Cremers, Thomas I F H
• Format: Journal Article
• Language: English
• Published: England 01.03.2009
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Analysis of Variance; Animals; Brain - cytology; Chromatography, High Pressure Liquid - methods; Citalopram - pharmacology; Drug Interactions; Electrochemistry - methods; Male; Microdialysis - methods; Neurons - drug effects; Neurons - physiology; Piperazines - pharmacology; Piperidines - pharmacology; Pyrazoles - pharmacology; Pyridines - pharmacology; Pyrrolidines - pharmacology; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A - physiology; Receptors, Serotonin - physiology; Serotonin - metabolism; Serotonin 5-HT1 Receptor Antagonists; Serotonin Agents - pharmacology; Serotonin Uptake Inhibitors - pharmacology; Tetrahydronaphthalenes - pharmacology; Tosyl Compounds - pharmacology; Wakefulness
• ISSN: 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05850.x

Both microdialysis and electrophysiology were used to investigate whether another serotonin (5-HT) receptor subtype next to the 5-HT(1A) 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-HT(7) receptors. Experiments were performed with the specific 5-HT(7) antagonist SB 258741 and the putative 5-HT(7) agonist AS19. In this study WAY 100.635 was used to block 5-HT(1A) 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-HT(7) 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-HT(7) receptors and moderate affinity for 5-HT(1A) receptors. The data are in support of an excitatory effect of selective serotonin reuptake inhibitors on 5-HT neuronal activity mediated by 5-HT(7) 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-HT(1A) receptors alone, in fact results from a shift in balance between 5-HT(1A) and 5-HT(7) receptor function.