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The Journal of Neuroscience, September 8, 2004, 24(36):7888-7894; doi:10.1523/JNEUROSCI.1506-04.2004

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Neurobiology of Disease
Uptake and Release of Norepinephrine by Serotonergic Terminals in Norepinephrine Transporter Knock-Out Mice: Implications for the Action of Selective Serotonin Reuptake Inhibitors

E. Sylvester Vizi,¹ Gabriella Zsilla,¹ Marc G. Caron,² and János P. Kiss¹

¹Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1450 Budapest, Hungary, and ²Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710

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 [³H]norepinephrine ([³H]NE) from hippocampal and cortical slices of NET^-/- knock-out (KO) and NET^+/+ wild-type (WT) mice and investigated the presynaptic 2-adenoceptor-mediated modulation of NE release in vitro and in vivo. The [³H]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 [³H]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 [³H]NE was taken up and released by serotonergic varicosities. This was further supported by the finding that the release of [³H]NE from hippocampal slices of KO mice was not modulated by the 2-adrenoceptor antagonist 7,8-(methylenedioxy)-14--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.

Key words: NET KO mice; norepinephrine; serotonin; uptake; citalopram; depression

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Received April 21, 2004; revised July 21, 2004; accepted July 21, 2004.

This article has been cited by other articles:

				L. Cervo, A. Canetta, E. Calcagno, S. Burbassi, G. Sacchetti, S. Caccia, C. Fracasso, D. Albani, G. Forloni, and R. W. Invernizzi Genotype-Dependent Activity of Tryptophan Hydroxylase-2 Determines the Response to Citalopram in a Mouse Model of Depression J. Neurosci., September 7, 2005; 25(36): 8165 - 8172. [Abstract] [Full Text] [PDF]

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