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 ≈4–5 × 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, thorough 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. © 1997 Elsevier Science Ltd.