Improved efficacy of fluoxetine in increasing hippocampal 5-hydroxytryptamine outflow in 5-HT(1B) receptor knock-out mice.
To test for the contribution of the 5-HT(1B) receptor subtype in mediating the effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), we used intracerebral in vivo microdialysis in awake, freely moving 5-HT(1B) receptor knock-out mice. We show that a single systemic administration of fluoxetine (1, 5 or 10 mg/kg, i.p.) increased extracellular serotonin levels [5-HT](ext) in the ventral hippocampus and frontal cortex of wild-type and mutant mice. However, in the ventral hippocampus, fluoxetine, at the three doses studied, induced a larger increase in [5-HT](ext) in knock-out than in wild-type mice. In the frontal cortex, the effect of fluoxetine did not differ between the two genotypes. The region-dependent response to fluoxetine described here in mutants confirms data we recently reported for another SSRI, paroxetine. These data suggest that 5-HT(1B) autoreceptors limit the effects of selective serotonin reuptake inhibitors on dialysate 5-HT levels at serotonergic nerve terminals located mainly in the ventral hippocampus. Alternative mechanisms, e.g., changes in 5-HT transporter and/or 5-HT(1A) receptor density in 5-HT(1B) receptor knock-out mice could also explain these findings.
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Laboratoire de Neuropharmacologie UPRES EAD MENRT, Faculté de Pharmacie IFR-ISIT Institut de Signalisation et d'Innovation Thérapeutique, Université Paris-Sud, Tour D1 2eme etage 5 rue 1-B.Clement, 92296, Châtenay-Malabry cedex, France.
David
Denis J
DJ
Jolliet
Pascale
P
Hen
René
R
Bourin
Michel
M
Gardier
Alain M
AM
D000818:Animals; D017660:Autoreceptors / Q000187:drug effects* / Q000235:genetics; D005473:Fluoxetine / Q000494:pharmacology*; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000235:genetics; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D017660:Autoreceptors; D005473:Fluoxetine; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors