Animals interact with their environment in a myriad of ways. One central component of this interaction is behavior. Critical for many behaviors are the neurobiological mechanisms for motivation, which depend on the neural reward pathway. If the outcome of a behavior is rewarding in some way, then the behavior will be reinforced by the reward pathway and subsequently will occur with heightened frequency or intensity or both. I characterized modifications in the reward pathway in lines of house mice selectively bred for high voluntary wheel running. I measured dopamine receptor densities in these high-runner (HR) mice and in non-selected control (C) lines in brain regions involved in reward and motor ability, characterized brain mass and volume, and juxtaposed competing rewards with wheel running to test incentive salience. I also assessed withdrawal symptoms in HR mice by comparing cardiovascular measures before, during, and following two weeks of wheel access. Finally, I administered an analog of erythropoietin (EPO) and measured hemoglobin (Hb) concentration, maximal aerobic capacity (<·>V</·>O2max), and wheel running to test whether further increases in running in the HR phenotype may be limited by oxygen (O2) transport or <·>V</·>O2max. Dopamine receptor densities did not differ between HR and C lines in the brain regions tested (caudate-putamen and prefrontal cortex). However, HR mice had higher brain masses (excluding cerebellum) when corrected for body mass, and larger midbrain volumes. When HR mice were given simultaneous access to wheels and solutions of artificial sweeteners, they consumed less of the artificial sweeteners than C mice suggesting an altered incentive salience for the sweet-taste reward. Additionally, HR mice displayed a reduction in blood pressure during withdrawal from running. Following EPO administration, [Hb] and <·>V</·>O2max were elevated, but not wheel running, suggesting that HR mice are not limited by O2 transport or <·>V</·>O2max.In conclusion, my research supports the hypothesis that the reward pathway is altered in HR mice. Also, my results provide evidence for both neurobiological and physiological changes that have evolved as components of the HR phenotype. Taken together, these findings offer new insight into the proximate control of behavior.