title: Exaggerated effect of fluvoxamine in heterozygote serotonin transporter knockout mice.
abstract: Clearance rates for serotonin (5-HT) in heterozygote (+/-) and homozygote (-/-) serotonin transporter (5-HTT) knockout (KO) mice have not been determined in vivo. Moreover, the effect of selective serotonin reuptake inhibitors (SSRIs) on 5-HT clearance in these mice has not been examined. In this study, the rate of clearance of exogenously applied 5-HT was measured in the CA3 region of the hippocampus of anesthetized mice using high-speed chronoamperometry. Compared with wild-type mice, the maximal rate of 5-HT clearance from extracellular fluid (ECF) was decreased in heterozygotes and more markedly so in KO mice. Heterozygote mice were more sensitive to the 5-HT uptake inhibitor, fluvoxamine, resulting in longer clearance times for 5-HT than in wild-type mice; as expected, the KO mice were completely unresponsive to fluvoxamine. There were no associated changes in norepinephrine transporter density, nor was there an effect of the norepinephrine uptake inhibitor, desipramine, on 5-HT clearance in any genotype. Thus, adaptive changes in the norepinephrine transport system do not occur in the CA3 region of hippocampus as a consequence of 5-HTT KO. These data highlight the potential of the heterozygote 5-HTT mutant mice to model the dynamic in vivo consequences of the human 5-HTT polymorphism.
authors.affiliation: Department of Psychiatry, University of Texas Health Science Center at San Antonio, USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Montañez
authors.forename: W Anthony
authors.initials: WA
authors.lastname: Owens
authors.forename: Georgianna G
authors.initials: GG
authors.lastname: Gould
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Murphy
authors.forename: Lynette C
authors.initials: LC
authors.lastname: Daws
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D016666:Fluvoxamine / Q000494:pharmacology*; D006579:Heterozygote; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006720:Homozygote; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012701:Serotonin / Q000008:administration & dosage / Q000493:pharmacokinetics; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D027981:Symporters / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D002352:Carrier Proteins; D003891:Desipramine; D016666:Fluvoxamine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; C493228:Slc6a2 protein, mouse; C493231:Slc6a4 protein, mouse