title: WAY100635-induced augmentation of the 5-HT-elevating action of citalopram: relative importance of the dose of the 5-HT1A (auto)receptor blocker versus that of the 5-HT reuptake inhibitor.
abstract: The elevation of extracellular 5-HT after systemic administration of 5-HT reuptake inhibiting drugs is strongly potentiated by agents capable of blocking 5-HT1A autoreceptors in the midbrain raphe. The present in vivo microdialysis study was aimed at assessing the relative importance of 5-HT reuptake inhibition versus 5-HT1A autoreceptor blockade in this interaction. Citalopram (0.5 or 5.0 mg/kg s.c.) dose-dependently increased dialysate 5-HT in the rat ventral hippocampus, maximally doubling the initial baseline values within 60 min after injection. The selective 5-HT1A receptor blocker, WAY100635 (0.01-0.3 mg/kg s.c.), further augmented, in a dose-dependent manner, the high-dose citalopram response (to approximately 4-5 x the pre-citalopram baseline). For comparison, the effect of low-dose (0.5 mg/kg s.c.) citalopram was mildly, but not significantly, potentiated by WAY100635 (0.3 mg/kg). WAY100635 given alone does not alter 5-HT under these conditions. The data confirm previous findings that 5-HT1A autoreceptor blockade enhances the citalopram-induced increase of extracellular 5-HT in the forebrain. To the extent the extracellular levels of 5-HT is a valid index, through 5-HT reuptake blockade appears to be the primary prerequisite for this interaction to occur. New drugs and/or treatment regimes based on the SSRI/5-HT1A autoreceptor blocker combination concept should, therefore, emphasize the former property.
authors.affiliation: Department of Pharmacology, University of Göteborg, Sweden. Stephan.Hjorth@pharm.gu.se
authors.forename: S
authors.initials: S
authors.lastname: Hjorth
authors.forename: D
authors.initials: D
authors.lastname: Westlin
authors.forename: H J
authors.initials: HJ
authors.lastname: Bengtsson
mesh_terms: D000818:Animals; D015283:Citalopram / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D015283:Citalopram; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D012701:Serotonin; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide