Serotonin 5‐HT1A Autoreceptor Blockade Potentiates the Ability of the 5‐HT Reuptake Inhibitor Citalopram to Increase Nerve Terminal Output of 5‐HT In Vivo: A Microdialysis Study

Abstract

The present study addressed the possibility that disinhibition of serotonin (5-HT) autoreceptor-mediated negative feedback might potentiate the elevation of nerve terminal 5-HT output induced by selective 5-HT reuptake blockade. To this end, rats were given citalopram and the 5-HT autoreceptor-blocking agents (S)-UH-301 (5-HT_1A) and (−)-penbutolol (5-HT_1A/1B), and the effect on extracellular 5-HT in the ventral hippocampus was monitored by means of in vivo microdialysis. Citalopram (5 mg/kg, s.c.) approximately doubled the 5-HT output, a response that was markedly augmented by (S)-UH-301 (3 mg/kg, s.c.) and (−)-penbutolol (8 mg/kg, s.c.) and by combined treatment with (S)-UH-301 (3 mg/kg, s.c.) plus (−)-penbutolol (1 μM; via the dialysis perfusion medium), but not by (−)-penbutolol (1 μM) alone. These findings provide evidence that 5-HT, in particular 5-HT_1A, autoreceptor-mediated negative feedback mechanisms are pivotal in determining the nerve terminal 5-HT output level after 5-HT reuptake inhibition. These findings have important implications for the interplay between different processes controlling 5-HT transmission in vivo and might possibly offer a lead toward novel, therapeutically exploitable principles.