title: Regional differences in the effect of the combined treatment of WAY 100635 and fluoxetine: an in vivo microdialysis study.
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 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.
authors.affiliation: Laboratoire de Neuropharmacologie JE MESR 92-372, Faculté de Pharmacie, Université Paris-Sud, Chatenay-Malabry 2, France.
authors.forename: I
authors.initials: I
authors.lastname: Malagié
authors.forename: A C
authors.initials: AC
authors.lastname: Trillat
authors.forename: E
authors.initials: E
authors.lastname: Douvier
authors.forename: M C
authors.initials: MC
authors.lastname: Anmella
authors.forename: M C
authors.initials: MC
authors.lastname: Dessalles
authors.forename: C
authors.initials: C
authors.lastname: Jacquot
authors.forename: A M
authors.initials: AM
authors.lastname: Gardier
mesh_terms: D000818:Animals; D005473:Fluoxetine / Q000494:pharmacology*; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D005473:Fluoxetine; D010879:Piperazines; D011725:Pyridines; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide