Long-term drug-induced alterations in gene expression underlying neuroplasticity in the nucleus accumbens (NAc) may play a crucial role in relapse behavior in abstinent drug addicts. In this respect, stimulus-induced relapse behavior is considered as the retrieval of stored drug-related information. Because the NAc shell may determine the impact of external and internal stimuli on goal-directed behavior, we compared long-term gene expression in this brain region after active and passive administration of different drugs of abuse. We made use of a preselected set of transcripts that were down-regulated 3 wk after active i.v. heroin self-administration. We found that most of these transcripts were not down-regulated long after passive exposure to the opiate. Most of the active heroin administration-regulated transcripts were also down-regulated in the NAc shell following active cocaine administration (common denominators). As observed with passive administration of heroin, passive exposure to cocaine was found to be relatively ineffective in reducing the expression of these transcripts. This work reveals that active drug consumption during self-administration (instrumental learning) is a crucial psychological factor directing long-term genomic responses in the brain.