Role of 5-HT1A receptors in the effects of acute and chronic fluoxetine on extracellular serotonin in the frontal cortex

Fluoxetine 10 mg/kg IP significantly increased the extracellular concentrations of serotonin (5-HT) in the frontal cortex as assessed by in vivo microdialysis. This effect was significantly potentiated when 0.3 mg/kg SC WAY-100635, a 5-HT_1A receptor antagonist, was administered 30 min before. WAY-100635 by itself had no effect on extracellular 5-HT. Twenty-four hours after chronic fluoxetine schedule (10 mg/kg/day IP x× 14 days), basal extracellular 5-HT concentrations in the frontal cortex were higher than those of animals that had received the vehicle chronically. At 24 h after the last dose, a challenge dose of fluoxetine (10 mg/kg IP) raised extracellular 5-HT similarly in chronically vehicle or fluoxetine treated rats. At this same interval 25 μg/kg SC 8-OH-DPAT, a 5-HT_1A receptor agonist, significantly reduced extracellular 5-HT only in the frontal cortex of rats treated chronically with the vehicle. Examining basal extracellular 5-HT, the effect of a challenge dose of fluoxetine and the effect of 25 μg/kg 8-OH-DPAT after 96 h washout, no differences were found between chronically fluoxetine and vehicle-treated rats. The results confirm that the ability of fluoxetine to stimulate 5-HT_1A autoreceptors through an increase of endogenous 5-HT attenuates its effect on cortical dialysate 5-HT. Chronic fluoxetine increased the basal concentrations of extracellular 5-HT only when a substantial amount of its metabolite was present in the brain and during the desensitization of presynaptic 5-HT_1A autoreceptors (24 h after the last dose). These effects, in fact, disappeared after 96 h washout. The continuous presence of the drug may, therefore, be necessary to maintain extracellular 5-HT at concentrations high enough to produce a therapeutic effect.