Mice lacking the norepinephrine transporter are supersensitive to psychostimulants.
The action of norepinephrine (NE) is terminated, in part, by its uptake into presynaptic noradrenergic neurons by the plasma-membrane NE transporter (NET), which is a target for antidepressants and psychostimulants. Disruption of the NET gene in mice prolonged the clearance of NE and elevated extracellular levels of this catecholamine. In a classical test for antidepressant drugs, the NET-deficient (NET-/-) animals behaved like antidepressant-treated wild-type mice. Mutants were hyper-responsive to locomotor stimulation by cocaine or amphetamine. These responses were accompanied by dopamine D2/D3 receptor supersensitivity. Thus altering NET expression significantly modulates midbrain dopaminergic function, an effect that may be an important component of the actions of antidepressants and psychostimulants.
Xu
F
F
Howard Hughes Medical Institute Laboratories, Departments of Cell Biology and Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Gainetdinov
R R
RR
Wetsel
W C
WC
Jones
S R
SR
Bohn
L M
LM
Miller
G W
GW
Wang
Y M
YM
Caron
M G
MG
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D017353:Gene Deletion; D006706:Homeostasis; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D050637:Receptors, Dopamine D3; D027981:Symporters; D009435:Synaptic Transmission / Q000187:drug effects
D000928:Antidepressive Agents; D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; C493594:Drd3 protein, mouse; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C493228:Slc6a2 protein, mouse; D027981:Symporters; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine; D009638:Norepinephrine