This study examined the effects of simultaneous variations in motivational state (food deprivation) and reinforcer magnitude (food presentation) on c-Fos immunoreactivity in the pre- and infralimbic medial prefrontal cortex (mPFC), nucleus accumbens (NAcc) core and shell, and dorsal striatum. In the first experiment, c-Fos was reliably increased in pre- and infralimbic mPFC of animals 12 and 36 h compared to 0 h deprived. In the second experiment, a small meal (2.5 g) selectively increased c-Fos immunoreactivity in both mPFC subdivisions of 36 h deprived animals, as well as in both NAcc subdivisions of 12 h deprived animals. Correlational analyses revealed a changing relationship between mPFC subregions and the NAcc compartments to which they project. In subjects 12 h deprived and allowed a small meal, c-Fos counts in prelimbic mPFC and NAcc core were positively correlated, as were those in infralimbic mPFC and NAcc shell (r=0.83 and 0.76, respectively). The opposite was true of animals 36 h deprived, with prelimbic mPFC/NAcc core and infralimbic mPFC/NAcc shell negatively correlated (r=-0.85 and -0.82, respectively). The third experiment examined the effects of unrestricted feeding (presentation of 20 g food) after 0, 12, or 36 h of deprivation. No differences between mean c-Fos counts were found, though prelimbic mPFC/NAcc core and mPFC/NAcc shell were positively correlated in animals 36 h deprived (r=0.76 and 0.89, respectively). These data suggest that the activity within the mPFC and NAcc, as well as the interaction between the two, changes as a complex combinatorial function of motivational state and reinforcer magnitude.