title: Serotonin uptake into dopamine neurons via dopamine transporters: a compensatory alternative.
abstract: Monoamine neurons are believed to use neuronal-specific transporters to remove their own transmitters from the extracellular space and thus terminate transmission to postsynaptic neurons. We report here, for the first time, conclusive evidence that a cross clearance of serotonin into dopamine neurons exists. Such alternative uptake by different neurons is adopted under circumstances when their own transporter function is no longer adequate. When the serotonin transporter (5-HTT) is disrupted in 5-HTT knockout mice, serotonin (5-HT) is found in dopamine (DA) neurons of homozygous (-/-) but not of heterozygous (+/-) mutant mice or their normal littermates. DA neurons containing 5-HT are seen in the substantia nigra and ventral tegmental area (VTA), but not in other brain areas of 5-HTT -/- mice. Normal rats treated with a 5-HT uptake blocker paroxetine also showed similar result. To verify the role of the DA transporter in such ectopic uptake, 5-HTT -/- mice were treated with DA uptake blocker GBR-12935, ectopic 5-HT in DA neurons was disappeared. These data indicate that: (a) 5-HT can be taken into DA neurons in rats and mice when the 5-HTT is not functionally adequate to remove extracellular 5-HT; (b) the 5-HT uptake into DA neurons is not affected by the 5-HT uptake blocker paroxetine; and (c) the DA transporter is responsible for the 5-HT uptake into DA neurons. This study thus demonstrates that cross neuronal type uptake exists and serves as a compensatory backup when a specific transporter is dysfunctional. This study also demonstrates that DA neurons can store 5-HT for possible "false neurotransmitter" or other usage.
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA. imce100@iupui.edu
authors.forename: Feng C
authors.initials: FC
authors.lastname: Zhou
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Murphy
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017374:Paroxetine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D004298:Dopamine; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017374:Paroxetine; D010879:Piperazines; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493231:Slc6a4 protein, mouse; C493232:Slc6a4 protein, rat; C044630:1-(2 (diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine