Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amphetamine / pharmacology
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Animals
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Antidepressive Agents / pharmacology*
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Behavior, Animal / drug effects
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Carrier Proteins / genetics*
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Carrier Proteins / physiology*
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Central Nervous System Stimulants / pharmacology*
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Cocaine / pharmacology
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Dopamine / metabolism
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Dopamine / pharmacology
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Dopamine Agonists / pharmacology
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Dose-Response Relationship, Drug
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Down-Regulation
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Gene Deletion*
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Homeostasis
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Mesencephalon / drug effects
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Mesencephalon / metabolism
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Mice
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Mice, Knockout
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Motor Activity / drug effects
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Norepinephrine / metabolism
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Norepinephrine Plasma Membrane Transport Proteins
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Receptors, Dopamine D2 / agonists
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Receptors, Dopamine D2 / metabolism
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Receptors, Dopamine D3
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Symporters*
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Synaptic Transmission / drug effects
Substances
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Antidepressive Agents
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Carrier Proteins
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Central Nervous System Stimulants
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Dopamine Agonists
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Drd3 protein, mouse
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Norepinephrine Plasma Membrane Transport Proteins
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Receptors, Dopamine D2
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Receptors, Dopamine D3
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Slc6a2 protein, mouse
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Symporters
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Amphetamine
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Cocaine
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Dopamine
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Norepinephrine