Abstract
We studied the changes in extracellular serotonin (5-HT) levels in the frontal cortex (FC) and ventral hippocampus (vHi) in conscious rats, induced by the combined administration of a highly selective 5-HT1A receptor antagonist, WAY 100635 (0.1 mg/kg, i.v.), and fluoxetine (1 mg/kg, i.p.), a selective 5-HT reuptake inhibitor (SSRI). In the two brain areas studied, no change in extracellular 5-HT concentrations was observed following fluoxetine administration over the 210 min post-injection period. However, in animals co-administered with [WAY 100635 + fluoxetine], the maximal increase in 5-HT levels in the FC was to 215% of the respective basal value (100%), while no significant change in 5-HT was observed in dialysates from the vHi. Furthermore, the [norfluoxetine]-to-[fluoxetine] ratio in the FC was significantly higher than in the hippocampus as measured in homogenates of animals treated with either fluoxetine alone or a prior administration of WAY 100635. Thus, WAY 100635 made the fluoxetine short-lasting effect apparent in the FC, but not by interfering with pharmacokinetic parameters of fluoxetine. Taken together, our data suggest the possibility, that either 5HT-1A autoreceptor sensitivity or uptake carrier density or higher [metabolite]-to-[parent drug] ratios in the FC than in the hippocampus may be involved in regional specific responses to SSRIs.
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Malagié, I., Trillat, AC., Douvier, E. et al. Regional differences in the effect of the combined treatment of WAY 100635 and fluoxetine: an in vivo microdialysis study. Naunyn-Schmiedeberg's Arch Pharmacol 354, 785–790 (1996). https://doi.org/10.1007/BF00166906
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DOI: https://doi.org/10.1007/BF00166906