In previous work we examined consequences of DAT and SERT KO on the functional connectivity of prefrontal cortex neuronal circuitry, brain morphology, and Y-27632 dihydrochloride metabolite levels. While there is some discussion about the exact definition of ‘reward circuits’, one generally accepted part of this idea includes a network linking brainstem and meso-corticallimbic structures. In this work we concentrate on the prefrontalventral striatopallidal circuit implicated in disorders involving the reward pathway and executive functions. Localized injection of manganese, an MR contrast agent well-established as a SB431542 inquirer circuitry tracer, into the prefrontal cortex followed by timelapse whole brain MR imaging enabled quantification of the functional connectivity of the circuitry. We have previously reported more robust connectivity between the PFC and posterior structures in SERT KO mice than in wildtype mice. In DAT KO mice the same procedure revealed preservation of cortico-striatalthalamic connectivity, but diminished robustness in reward circuitry distal to the thalamus. Structural and metabolic MR analysis revealed no significant differences between these knockouts and wildtype controls. Hence we concluded that lifelong transporter deficits primarily affect the degree of activity in these circuits without major large scale anatomical or metabolic disturbances. Here we extend this investigation to the NET KO mouse using the same experimental approach as for the other two monoamine transporter knockout strains, which completes our examination of the effects of gene knockout of the three major molecular targets of cocaine. Magnetic resonance spectroscopy of the striatum was used to measure the concentration of several small molecule metabolites present at millimolar or greater concentrations that have been associated with disease states. Diffusion tensor imaging was employed to investigate differences in brain structure between NET KO and WT littermate mice using tensor based morphometry to identify local structural differences between the KO and WT mice. This study reports the effects of life-long deletion of NET on metabolite levels, brain structure and neuronal connectivity in the meso-cortical-limbic reward circuitry. These findings are discussed in the context of similar work in previous studies using SERT and DAT KO mice, providing a unique framework to consider the roles of these neurotransmitters in brain function and dysfunction. In this study we investigated how mice with lifelong genetic deletion of the norepinephrine transporter differ from their wildtype littermates in aspects of metabolite levels, brain morphology and neuronal circuitry associated with reward pathways. We employed a panel of magnetic resonance methods with voxelwise analyses, as well as histological confirmation. This work extends earlier examinations of serotonin and dopamine transporter knockout mice. Interactions between the dopaminergic, serotonergic and noradrenergic systems are well known. Comparison of differences detected by MEMRI in the reward circuitry of mouse strains with deletion of each of the three monoamine transporters emphasizes the synergistic complexity of these overlapping integrated systems. We 
used MRS to measure metabolite levels averaged over an 8 ml volume centered in the striatum. Only N-acetyl aspartate levels differed between the NET KO and wildtype mice.