Development of drug addiction is accompanied by the induction of long-lasting neurobiological changes. Dopamine D1 receptors are involved in mediating cocaine-induced neuroadaptation, yet the underlying intracellular mechanisms remain less clear. Using a genetically modified mouse in which Fos is primarily mutated in D1 receptor-bearing neurons in the brain, we examined a potential role of the immediate early gene Fos, which is rapidly induced by cocaine via D1 receptors, in mediating cocaine-induced persistent neurobiological changes. We found that the composition of AP-1 transcription complexes and expression levels of AP-1 complexes, and several transcription factors, neurotransmitter receptors as well as intracellular signaling molecules following repeated cocaine administration are altered in Fos-deficient brains. Moreover, dendritic reorganization of medium spiny neurons induced by repeated exposure to cocaine is attenuated in the mutant brains. The mutant mice also exhibit reduced behavioral sensitization after repeated cocaine administration. These findings suggest that c-Fos expressed in D1 receptor-bearing neurons mediates cocaine-induced persistent changes.