It is known that negative environmental conditions increase vulnerability to drugs, whereas little is known on whether positive environmental conditions such as enriched environments (EE) have protective effects against addiction. We have previously found that EE consisting of bigger cages containing several toys that were changed once per week reduce cocaine-induced increases in locomotor activity. Here, we also show that the rewarding effects of cocaine are blunted in mice reared from weaning to adulthood in EE compared to mice reared in standard environments (SE). In addition, although both EE and SE mice develop behavioral sensitization to cocaine, EE mice show less activation in response to repeated administration of cocaine injections and reduced responses to cocaine challenges. In vivo microdialysis experiments demonstrate that the protective effects of EE do not depend on reduced cocaine-induced increases in the dopamine levels in the ventral or dorsal striatum. On the other hand, they were associated with reduced cocaine-induced expression of the immediate early gene zif-268 in the nucleus accumbens (shell and core) of EE mice. Finally, basal levels of Delta-Fos B, a transcription factor known to be increased by sustained activation of striatal neurons, are higher in the striatum of EE compared to SE mice and repeated administration of cocaine increases Delta-Fos B levels in SE mice but decreases them in EE mice. Altogether our results demonstrate that exposure to complex environments during early stages of life produce dramatic changes in the striatum that result in reduced reactivity to drugs of abuse.