Regulation of norepinephrine transporter abundance by catecholamines and desipramine in vivo.
The norepinephrine transporter (NET) regulates adrenoreceptor signaling by controlling the availability of synaptic norepinephrine (NE), and it is a direct target for some classes of antidepressant drugs. NET levels are normal in dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack NE, demonstrating that the NET does not require endogenous NE for appropriate regulation under physiological conditions. In contrast, tyrosine hydroxylase knockout (Th -/-) mice that lack both NE and dopamine (DA) have reduced levels of NET, suggesting that it is down-regulated by a complete absence of catecholamines and not NE per se. Chronic treatment with the NET inhibitor, desipramine (DMI), reduced NET levels in both control and Dbh -/- mice, demonstrating that NE is not required for the regulation of NET by antidepressant drugs. There are some qualitative and quantitative differences in the down-regulation of the NET by catecholamine depletion and DMI treatment, suggesting that different mechanisms may be involved.
Howard Hughes Medical Institute, Box 357370, University of Washington, Seattle 98195, USA. dzw@genetics.washington.edu
David
D
Weinshenker
Sylvia S
SS
White
Martin A
MA
Javors
Richard D
RD
Palmiter
Patricia
P
Szot
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D002395:Catecholamines / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency / Q000235:genetics; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D027981:Symporters / Q000096:biosynthesis / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000172:deficiency / Q000235:genetics
D018759:Adrenergic Uptake Inhibitors; D002395:Catecholamines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; C493228:Slc6a2 protein, mouse; D027981:Symporters; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D003891:Desipramine; D004298:Dopamine; D009638:Norepinephrine