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.
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.
Bosker
Fokko J
FJ
Department of Pharmacy, Biomonitoring & Sensoring, University of Groningen, The Netherlands. f.j.bosker@psy.umcg.nl
Folgering
Joost H A
JH
Gladkevich
Anatoliy V
AV
Schmidt
Anne
A
van der Hart
Marieke C G
MC
Sprouse
Jeffrey
J
den Boer
Johan A
JA
Westerink
Ben H C
BH
Cremers
Thomas I F H
TI
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000166:cytology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D015283:Citalopram / Q000494:pharmacology; D004347:Drug Interactions; D004563:Electrochemistry / Q000379:methods; D008297:Male; D017551:Microdialysis / Q000379:methods; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists; D018490:Serotonin Agents / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014105:Tosyl Compounds / Q000494:pharmacology; D014851:Wakefulness
D015283:Citalopram; D010879:Piperazines; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D011759:Pyrrolidines; D044282:Receptor, Serotonin, 5-HT1A; D011985:Receptors, Serotonin; D012701:Serotonin; D058829:Serotonin 5-HT1 Receptor Antagonists; D018490:Serotonin Agents; D017367:Selective Serotonin Reuptake Inhibitors; D013764:Tetrahydronaphthalenes; D014105:Tosyl Compounds; C522380:5-HT(7) receptor, rat; C505862:AS 19 compound; C462239:SB258741; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide