title: Subanesthetic doses of ketamine transiently decrease serotonin transporter activity: a PET study in conscious monkeys.
abstract: Subanesthetic doses of ketamine, an N-methyl-D-aspartic acid (NMDA) antagonist, have a rapid antidepressant effect which lasts for up to 2 weeks. However, the neurobiological mechanism regarding this effect remains unclear. In the present study, the effects of subanesthetic doses of ketamine on serotonergic systems in conscious monkey brain were investigated. Five young monkeys underwent four positron emission tomography measurements with [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile ([(11)C]DASB) for the serotonin transporter (SERT), during and after intravenous infusion of vehicle or ketamine hydrochloride in a dose of 0.5 or 1.5 mg/kg for 40 min, and 24 h post infusion. Global reduction of [(11)C]DASB binding to SERT was observed during ketamine infusion in a dose-dependent manner, but not 24 h later. The effect of ketamine on the serotonin 1A receptor (5-HT1A-R) and dopamine transporter (DAT) was also investigated in the same subjects studied with [(11)C]DASB. No significant changes were observed in either 5-HT1A-R or DAT binding after ketamine infusion. Microdialysis analysis indicated that ketamine infusion transiently increased serotonin levels in the extracellular fluid of the prefrontal cortex. The present study demonstrates that subanesthetic ketamine selectively enhanced serotonergic transmission by inhibition of SERT activity. This action coexists with the rapid antidepressant effect of subanesthetic doses of ketamine. Further studies are needed to investigate whether the transient combination of SERT and NMDA reception inhibition enhances each other's antidepressant actions.
authors.affiliation: Central Research Laboratory, Hamamatsu Photonics KK, Hamakita, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohba
authors.forename: Shingo
authors.initials: S
authors.lastname: Nishiyama
authors.forename: Norihiro
authors.initials: N
authors.lastname: Harada
authors.forename: Takeharu
authors.initials: T
authors.lastname: Kakiuchi
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukada
authors.forename: Edward F
authors.initials: EF
authors.lastname: Domino
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001596:Benzylamines / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects*; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003243:Consciousness; D018765:Dopamine Uptake Inhibitors / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D007091:Image Processing, Computer-Assisted; D007649:Ketamine / Q000494:pharmacology*; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D017551:Microdialysis; D049268:Positron-Emission Tomography; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*
chemical_list: D000700:Analgesics; D001596:Benzylamines; D002247:Carbon Isotopes; D018765:Dopamine Uptake Inhibitors; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; D050486:Serotonin Plasma Membrane Transport Proteins; D019788:Fluorodeoxyglucose F18; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D007649:Ketamine; D003042:Cocaine