Uptake and release of norepinephrine by serotonergic terminals in norepinephrine transporter knock-out mice: implications for the action of selective serotonin reuptake inhibitors.
Our aim was to investigate the functional properties of the noradrenergic system in genetically modified mice lacking the norepinephrine transporter (NET). We measured the uptake and release of [(3)H]norepinephrine ([(3)H]NE) from hippocampal and cortical slices of NET(-/-) knock-out (KO) and NET(+/+) wild-type (WT) mice and investigated the presynaptic alpha2-adenoceptor-mediated modulation of NE release in vitro and in vivo. The [(3)H]NE uptake was reduced to 12.6% (hippocampus) and 33.5% (frontal cortex) of WT control in KO mice. The neuronal component of this residual uptake was decreased by 79.4 and 100%, respectively, when a selective serotonin reuptake inhibitor (SSRI) citalopram was present during the loading. The more preserved neuronal release of [(3)H]NE (hippocampus, 28.1%; frontal cortex, 74.4%; compared with WT) almost completely disappeared in both regions (94.1 and 95.3% decrease compared with KO, respectively) in the presence of citalopram, suggesting that [(3)H]NE was taken up and released by serotonergic varicosities. This was further supported by the finding that the release of [(3)H]NE from hippocampal slices of KO mice was not modulated by the alpha2-adrenoceptor antagonist 7,8-(methylenedioxy)-14-alpha-hydroxyalloberbane HCl, whereas the endogenous release of NE measured by microdialysis was even more efficiently enhanced by this drug in NET-deficient mice. These experiments indicate that serotonergic varicosities can accumulate and release NE as a result of the heterologous uptake of transmitters. Because the diffusion of NE may be spatially limited by serotonin transporters, the SSRIs, despite their selectivity, might enhance not only serotonergic but also noradrenergic neurotransmission, which might contribute to their antidepressant action.
Vizi
E Sylvester
ES
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1450 Budapest, Hungary. esvizi@koki.hu
Zsilla
Gabriella
G
Caron
Marc G
MG
Kiss
János P
JP
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001599:Berberine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009928:Organ Specificity; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D018341:Receptors, Adrenergic, alpha-2; D050486:Serotonin Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; C493231:Slc6a4 protein, mouse; D027981:Symporters; D005473:Fluoxetine; D001599:Berberine; C048886:7,8-(methylenedioxy)-14-hydroxyberbane; C011386:nisoxetine; D009638:Norepinephrine