REGIONAL DIFFERENCES IN THE EFFECT OF THE COMBINED TREATMENT OF WAY-100635 AND FLUOXETINE - AN IN-VIVO MICRODIALYSIS STUDY

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 re ceptor 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 brai n areas studied, no change in extracellular 5-HT concentrations was ob served following fluoxetine administration over the 210 min post-injec tion period. However, in animals co-administered with [WAY 100635 + fl uoxetine], the maximal increase in 5-HT levels in the FC was to 215% o f the respective basal value (100%), while no significant change in 5- HT was observed in dialysates from the vHi. Furthermore, the [norfluox etine]-to-[fluoxetine] ratio in the FC was significantly higher than i n the hippocampus as measured in homogenates of animals treated with e ither 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 5-HT1A autoreceptor sensitivity or uptake carrier density or higher [metabol ite]-to-[parent drug] ratios in the FC than in the hippocampus may be involved in regional specific responses to SSRIs.