Synergistic neurochemical and behavioral effects of fluoxetine and 5-HT1A receptor antagonists.

We studied the ability of WAY 100635 [N-[4-(2-methoxyphenyl)-1-piperazinyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide], 0.5 mg/kg, i.v. and (-)-5-Me-8-OH-DPAT [(-)-5-methyl-8-hydroxy-2-(di-n-propylamino)tetralin], 3 mg/kg, i.v. two selective 5-HT1A receptor antagonists, to potentiate: (1) the enhancement of extracellular 5-HT levels ([5-HT(ext)]) induced by a single administration of 5 mg/kg i.p. fluoxetine using in vivo microdialysis in the ventral hippocampus of conscious rats, (2) the decrease in food intake induced by this antidepressant drug in food-deprived rats. The effects of fluoxetine were significantly potentiated, by 30-40%, by WAY 100635 as well as by (-)-5-Me-8-OH-DPAT in the two sets of experiments. Thus, fluoxetine increased [5-HT(ext)] in serotonergic nerve terminal areas and consequently, induced hypophagia, both effects being limited by indirect activation of somatodendritic 5-HT1A autoreceptors.

Regulation of serotonin release in the frontal cortex and ventral hippocampus of homozygous mice lacking 5-HT1B receptors: in vivo microdialysis studies.

To assess the involvement of the serotonin receptor subtype 5-HT1B as terminal autoreceptor regulating 5-HT release in mice, we compared basal values and potassium-evoked changes of extracellular 5-HT levels obtained by in vivo microdialysis in two serotoninergic terminal projection areas of conscious wild-type mice with those measured in homozygous mutant mice lacking the gene encoding the 5-HT1B receptor. In the frontal cortex and ventral hippocampus, basal and K+-evoked 5-HT release did not differ between the two strains of mice studied. The infusion via reverse microdialysis of the selective 5-HT1B receptor agonist CP-93,129 (500 nM) decreased significantly K+-evoked 5-HT release in the frontal cortex (by -44%) and ventral hippocampus (by -32%) of wild-type mice but had no effect in mutants. In a similar manner, the mixed 5-HT1B-5-HT1D receptor agonist sumatriptan (800 nM) decreased significantly K+-evoked 5-HT release in the frontal cortex (by -46%) of wild-type mice but had no effect in mutants. These results demonstrated that 5-HT1B knockout mice are not as sensitive to full (CP-93,129) and mixed (sumatriptan) 5-HT1B receptor agonists as are wild-type mice. These data provide in vivo evidence that, in mice, 5-HT1B, but not 5-HT1D, autoreceptors inhibit 5-HT release at nerve terminals located in the frontal cortex and ventral hippocampus.

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 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 5-HT1A 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.