title: Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters.
abstract: Cocaine conditioned place preference (CPP) is intact in dopamine transporter (DAT) knockout (KO) mice and enhanced in serotonin transporter (SERT) KO mice. However, cocaine CPP is eliminated in double-KO mice with no DAT and either no or one SERT gene copy. To help determine mechanisms underlying these effects, we now report examination of baselines and drug-induced changes of extracellular dopamine (DAex) and serotonin (5-HT(ex)) levels in microdialysates from nucleus accumbens (NAc), caudate putamen (CPu), and prefrontal cortex (PFc) of wild-type, homozygous DAT- or SERT-KO and heterozygous or homozygous DAT/SERT double-KO mice, which are differentially rewarded by cocaine. Cocaine fails to increase DAex in NAc of DAT-KO mice. By contrast, systemic cocaine enhances DAex in both CPu and PFc of DAT-KO mice though local cocaine fails to affect DAex in CPu. Adding SERT to DAT deletion attenuates the cocaine-induced DAex increases found in CPu, but not those found in PFc. The selective SERT blocker fluoxetine increases DAex in CPu of DAT-KO mice, while cocaine and the selective DAT blocker GBR12909 increase 5-HT(ex) in CPu of SERT-KO mice. These data provide evidence that (a) cocaine increases DAex in PFc independently of DAT and that (b), in the absence of SERT, CPu levels of 5-HT(ex) can be increased by blocking DAT. Cocaine-induced alterations in CPu DA levels in DAT-, SERT-, and DAT/SERT double-KO mice appear to provide better correlations with cocaine CPP than cocaine-induced DA level alterations in NAc or PFc.
authors.affiliation: Department of Molecular Psychiatry, Tokyo Institute of Psychiatry, Japan.
authors.forename: Hao-Wei
authors.initials: HW
authors.lastname: Shen
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hagino
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Keiko
authors.initials: K
authors.lastname: Shinohara-Tanaka
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
authors.forename: Hideko
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Murphy
authors.forename: F Scott
authors.initials: FS
authors.lastname: Hall
authors.forename: George R
authors.initials: GR
authors.lastname: Uhl
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sora
mesh_terms: D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000378:metabolism; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D013238:Stereotaxic Techniques
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D050486:Serotonin Plasma Membrane Transport Proteins; C493215:Slc6a3 protein, mouse; C493231:Slc6a4 protein, mouse; D005473:Fluoxetine; D012701:Serotonin; C043425:vanoxerine; D003042:Cocaine; D004298:Dopamine