Systemic cocaine induces c-fos expression in rat striatum. The functional role of this phenomenon remains unknown. Recently, selective inhibition of gene expression in the brain using antisense oligodeoxynucleotides became possible. Here, we report that bilateral administration of an antisense oligo against c-fos in the nucleus accumbens blocks cocaine induced locomotor stimulation, without affecting spontaneous exploratory activity. A control sense oligo was inactive. This finding suggests a role for c-fos in mediating psychostimulant effects of cocaine.