Rapid activation of transcription factor genes is thought to play a key role in stimulus-induced neuronal plasticity. To help understand the genomic response that may underlie long-term effects of cocaine and amphetamine, we have investigated the effect of these agents on Zif268, a transcription regulatory factor that is expressed at high levels in brain neurons. Like c-fos, zif268 is markedly activated in striatum by cocaine and amphetamine. This response appears to involve the dopamine system, since it is abolished by SCH23390, a selective D1 dopamine receptor antagonist, or by 6-hydroxydopamine lesions. To assess the role of other monoamine systems in regulating the expression of these transcription factors, we have examined the effects of selective monoamine uptake blockers as well as agents that lesion the norepinephrine and serotonin systems. These studies indicate that, in addition to the dopamine system, the norepinephrine and serotonin systems also play prominent roles in the activation of zif268 and c-fos by cocaine and amphetamine.