Mice lacking the norepinephrine transporter ave supersensitive to psychostimulants

The action of norepinephrine (NE) is terminated, in part, by its uptake int o presynaptic noradrenergic neurons by the plasma-membrane NE transporter ( NET), which is a target for antidepressants and psychostimulants. Disruptio n of the NET gene in mice prolonged the clearance of NE and elevated extrac ellular levels of this catecholamine. In a classical test for antidepressan t drugs, the NET-deficient (NET-/-) animals behaved like antidepressant-tre ated wild-type mice. Mutants were hyper-responsive to locomotor stimulation by cocaine or amphetamine. These responses were accompanied by dopamine D- 2/D-3 receptor supersensitivity. Thus altering NET expression significantly modulates midbrain dopaminergic function, an effect that may be an importa nt component of the actions of antidepressants and psychostimulants.