Opiates and psychostimulants produce many shared behavioral and neurobiological adaptations, such as behavioral sensitization and the induction of immediate early genes in the caudate-putamen (CPu). Previous studies indicate that factors such as dose, the environmental context surrounding drug administration and drug history can influence both morphine- and psychostimulant-induced behavioral sensitization. In addition, these factors can modulate the ability of psychostimulants to engage striatofugal circuits in the CPu. The present study, therefore, sought to examine whether these factors have similar influences over the ability of morphine to engage cortico-striatofugal circuits. We report that, when given in the home cage, morphine produced a small, but significant increase in the number of c-fos+ striatonigral cells and c-fos+ cells in cingulate cortex, but had no effect on the number of c-fos+ striatopallidal cells. When given in a novel test environment, however, morphine dramatically increased the number of c-fos+ striatonigral cells in a dose-dependent fashion, and this effect was maintained following repeated treatment. Unexpectedly, morphine treatment in a novel environment produced a dose-dependent reduction in the number of c-fos+ striatopallidal cells and c-fos+ cells in cingulate cortex, relative to exposure to novelty alone-effects that were reversed by repeated morphine treatment. We suggest that alterations in c-fos expression patterns in striatofugal circuits following morphine administration may be involved in drug-experience-dependent plasticity.