Mice Expressing Cocaine‐Insensitive Norepinephrine Transporters Display Supersensitive Cocaine‐Induced Locomotor Activity

Abstract

Cocaine exerts its psychostimulant effects by inhibiting the function of the membrane transporters for dopamine, serotonin, and norepinephrine. Although the role of the dopamine transporter in cocaine addiction is well‐established, the role of the norepinephrine transporter (NET) is unclear. Our laboratory has shown that mutating amino acid residues F101C‐A105G‐N153T within transmembrane 2 of NET results in a functional NET that has a reduction in cocaine sensitivity (i.e. cocaine IC50 reduced by 37 fold). To explore the role of NET in cocaine addiction, we produced knockin mice expressing this mutant cocaine‐insensitive NET (NET‐CI mice). In this preliminary study, we used these animals to investigate cocaine‐induced locomotor stimulation and reward. NET‐CI mice had reduced locomotor activity in general as estimated in an open filed assay, but they were 50% more responsive to the locomotor stimulating effects of cocaine (10 and 20 mg/kg) than control mice. NET‐CI mice did not appear to show significant differences in cocaine reward‐related behaviors as measured by conditioned place preference. These data show that without NET inhibition cocaine's stimulating effects are enhanced while its rewarding effects appear to remain unaltered. The NET‐CI mice may offer an improved tool for studying the role of NET in cocaine addiction.